Zespół ostrej niewydolności oddechowej
Patofizjologia i mechanizm

Zespół ostrej niewydolności oddechowej (ARDS) charakteryzuje się rozlanym uszkodzeniem bariery pęcherzykowo-włośniczkowej, prowadzącym do obrzęku płuc niekardiogennego i opornej na tlenoterapię hipoksemii. Patogeneza ARDS obejmuje nadmierną reakcję zapalną z uwolnieniem cytokin prozapalnych (TNF-α, IL-1, IL-6, IL-8), aktywację neutrofili i produkcję reaktywnych form tlenu (ROS) oraz azotu (RNS), co skutkuje uszkodzeniem śródbłonka i nabłonka pęcherzykowego. Uszkodzenie pneumocytów typu I i II prowadzi do zwiększonego napływu płynu do pęcherzyków oraz zmniejszonej produkcji surfaktantu, co pogarsza wymianę gazową i powoduje ciężką hipoksemię. Dodatkowo, aktywacja układu krzepnięcia i immunotromboza nasilają uszkodzenie naczyń płucnych, przyczyniając się do powstania mikroskrzepów i nadciśnienia płucnego, które pogarszają perfuzję i funkcję prawokomorową serca.

  1. Patofizjologia Zespołu Ostrej Niewydolności Oddechowej
    1. Ogólny mechanizm uszkodzenia płuc w ARDS
    2. Rola zapalenia w patogenezie ARDS
    3. Uszkodzenie bariery pęcherzykowo-włośniczkowej
    4. Rola procesów śmierci komórkowej
    5. Rola stresu oksydacyjnego
    6. Rola immunotrombozy
    7. Fazy ARDS
    8. Rola makrofagów i neutrofili
    9. Rola układu krzepnięcia
    10. Rola uszkodzenia płuc wywołanego przez respirator
    11. Uszkodzenie mechanotransdukcyjne
    12. Zaburzenia usuwania płynu pęcherzykowego
    13. Nadciśnienie płucne w ARDS
    14. Patomechanizm hipoksemii w ARDS
    15. Różnice w patogenezie zależne od etiologii
    16. Rola czynników genetycznych
    17. Podsumowanie patogenezy ARDS
    18. Kolejne rozdziały

Patofizjologia Zespołu Ostrej Niewydolności Oddechowej

Zespół ostrej niewydolności oddechowej (ARDS) to ciężka forma niewydolności oddechowej charakteryzująca się rozlanym uszkodzeniem pęcherzyków płucnych, oporną na tlenoterapię hipoksemią i obrzękiem płuc niekardiogennym. Początkowo opisany w 1967 roku, ARDS pozostaje stanem zagrażającym życiu, z heterogenicznym obrazem klinicznym, wynikającym z kompleksowych mechanizmów patofizjologicznych.12 Zrozumienie patogenezy ARDS jest kluczowe dla opracowania skutecznych strategii terapeutycznych i zmniejszenia śmiertelności związanej z tym zespołem.

Ogólny mechanizm uszkodzenia płuc w ARDS

ARDS rozwija się w odpowiedzi na bezpośrednie lub pośrednie uszkodzenie płuc, które inicjuje niekontrolowaną reakcję zapalną. Kluczowym elementem patogenezy jest uszkodzenie bariery pęcherzykowo-włośniczkowej, składającej się z nabłonka pęcherzykowego i śródbłonka naczyń włosowatych.12 Uszkodzenie to prowadzi do zwiększonej przepuszczalności naczyń i nabłonka pęcherzykowego, powodując gromadzenie się płynu bogatego w białko w przestrzeni pęcherzykowej, co skutkuje obrzękiem płuc, zaburzeniami wymiany gazowej i ciężką hipoksemią.3

ARDS może być wywołany przez bezpośrednie uszkodzenie płuc (np. zapalenie płuc, aspiracja treści żołądkowej, uraz bezpośredni) lub pośrednie (np. sepsa, uraz wielonarządowy, pancreatitis, przetoczenia krwi).45 Niezależnie od czynnika inicjującego, patofizjologiczne manifestacje ARDS są podobne i obejmują dysfunkcję bariery pęcherzykowo-włośniczkowej, zaburzenia usuwania płynu pęcherzykowego oraz uszkodzenie oksydacyjne wynikające z niekontrolowanej reakcji zapalnej.6

Rola zapalenia w patogenezie ARDS

Centralnym elementem patogenezy ARDS jest dysregulacja procesów zapalnych. Gdy płuca zostają uszkodzone przez infekcję, uraz lub stany zapalne, aktywowane są szlaki zapalne.7 Proces zapalny, chociaż początkowo korzystny dla eliminacji patogenów, przy nadmiernej aktywacji prowadzi do uszkodzenia pęcherzyków i zwiększonej przepuszczalności śródbłonka i nabłonka, co skutkuje gromadzeniem się płynu bogatego w białko w pęcherzykach płucnych.8

Kluczowym elementem patofizjologii ARDS jest tzw. „burza cytokinowa”, charakteryzująca się uwolnieniem licznych cytokin prozapalnych, w tym czynnika martwicy nowotworów alfa (TNF-α), interleukiny-1 (IL-1), IL-6 i IL-8. Cytokiny te aktywują szlaki sygnałowe, takie jak czynnik jądrowy-κB (NF-κB) i przekaźnik sygnału i aktywator transkrypcji 3 (STAT3), prowadząc do zwiększenia przepuszczalności naczyń, zaburzenia bariery pęcherzykowo-włośniczkowej i obrzęku płuc.9

W odpowiedzi na uszkodzenie, neutrofile gromadzą się w mikrokrążeniu płucnym i ulegają aktywacji, prowadząc do degranulacji i uwolnienia mediatorów toksycznych, w tym proteaz, reaktywnych form tlenu, cytokin prozapalnych i czynników prokoagulacyjnych. Te mediatory powodują zwiększenie przepuszczalności naczyń i trwałą utratę prawidłowej funkcji barierowej śródbłonka.10

Mediatory zapalne w ARDS obejmują:

  • Cytokiny prozapalne (TNF-α, IL-1β, IL-6, IL-8)
  • Neutrofile i ich produkty (elastaza neutrofilowa, mieloperoksydaza, sieci zewnątrzkomórkowe neutrofili – NETs)
  • Reaktywne formy tlenu (ROS) i azotu (RNS)
  • Czynniki aktywujące płytki krwi
  • Czynniki prokoagulacyjne
  • Czynnik wzrostu śródbłonka naczyniowego (VEGF)

111213

Uszkodzenie bariery pęcherzykowo-włośniczkowej

Bariera pęcherzykowo-włośniczkowa składa się z dwóch głównych komponentów: śródbłonka naczyń włosowatych i nabłonka pęcherzykowego. Uszkodzenie obu tych elementów przyczynia się do rozwoju ARDS.1415

Uszkodzenie śródbłonka naczyniowego

Uszkodzenie śródbłonka naczyń płucnych jest kluczowym czynnikiem inicjującym ARDS. Nadmierne uwalnianie trombiny, TNF-α, VEGF i sygnałów leukocytarnych destabilizuje połączenia VE-kadherynowe w śródbłonku, co prowadzi do zwiększonej przepuszczalności śródbłonka i gromadzenia się płynu pęcherzykowego.16 Uszkodzenie śródbłonka może być wywołane przez różne mechanizmy, przy czym uszkodzenie zależne od neutrofili jest prawdopodobnie najlepiej udokumentowaną ścieżką.17

Chociaż uszkodzenie śródbłonka płucnego jest niezbędne do rozwoju obrzęku płuc bogatego w białko w ARDS, samo w sobie zwykle nie jest wystarczające do wywołania zespołu ARDS bez pewnego stopnia uszkodzenia nabłonka płucnego.18

Uszkodzenie nabłonka pęcherzykowego

Bariera nabłonka pęcherzykowego jest podobna do swojego odpowiednika śródbłonkowego, ale posiada połączenia E-kadherynowe zamiast VE-kadherynowych i jest znacznie mniej przepuszczalna.19 W warunkach patologicznych migracja neutrofili powoduje uszkodzenie nabłonka poprzez rozrywanie połączeń międzykomórkowych, apoptozę i obnażenie, co ostatecznie prowadzi do zwiększonej przepuszczalności nabłonka.20

Nabłonek pęcherzykowy składa się z dwóch typów komórek: pneumocytów typu I, które stanowią 90% powierzchni nabłonka i są łatwo uszkadzane, oraz pneumocytów typu II, które są stosunkowo bardziej odporne na uszkodzenia, ale pełnią kluczowe funkcje, w tym produkcję surfaktantu, transport jonów oraz proliferację i różnicowanie się w komórki typu I po uszkodzeniu komórkowym.21

Uszkodzenie komórek typu I prowadzi do zwiększonego napływu płynu do pęcherzyków oraz zmniejszonego usuwania płynu z przestrzeni pęcherzykowej. Uszkodzenie komórek typu II skutkuje zmniejszoną produkcją surfaktantu, co prowadzi do zmniejszonej podatności płuc i zapadania się pęcherzyków.2223

Stres oksydacyjny i burza cytokinowa indukują apoptozę i nekrozę komórek nabłonkowych, co upośledza funkcję barierową i prowadzi do gromadzenia się płynu w pęcherzykach płucnych oraz rozwoju obrzęku płuc.24

Rola procesów śmierci komórkowej

Śmierć komórkowa odgrywa kluczową rolę w progresji ARDS, głównie poprzez apoptozę, nekrozę i pyroptozę. Apoptoza, będąca ściśle regulowaną formą programowanej śmierci komórkowej, jest niezbędna do eliminacji uszkodzonych lub zainfekowanych komórek, zapobiegając rozprzestrzenianiu się zapalenia. Jednak nadmierna apoptoza może upośledzić zdolność płuc do regeneracji.25

Reaktywne formy tlenu uwalniane w odpowiedzi na cytokiny zapalne indukują apoptozę i nekroptozę w ARDS.26 Te procesy śmierci komórkowej przyczyniają się do uszkodzenia nabłonka i śródbłonka, prowadząc do zwiększonej przepuszczalności i obrzęku płuc.

Rola stresu oksydacyjnego

W ARDS nadmierne uwalnianie reaktywnych form tlenu (ROS) i reaktywnych form azotu (RNS) indukuje uszkodzenia oksydacyjne błon komórkowych i białek, co upośledza funkcję i integralność komórek. Prowadzi to do dysfunkcji bariery śródbłonkowej i nabłonkowej, zwiększonej przepuszczalności naczyń i ostatecznie obrzęku płuc.27

Stres oksydacyjny, wynikający z produkcji ROS, odgrywa ważną rolę w progresji ARDS i uszkodzeniu płuc. Nadmierne wytwarzanie ROS jest uznawane za przyczynę patogenezy i progresji ARDS. Obecne zrozumienie mechanizmu ochronnego obejmuje szlak czynnika jądrowego erytroidalnego 2 (Nrf2) przeciwko stresowi oksydacyjnemu.2829

Rola immunotrombozy

Zapalenie i aktywowane komórki śródbłonka wyzwalają kaskady koagulacyjne i aktywację płytek krwi, generujące stan prokoagulacyjny zarówno w przestrzeni powietrznej, jak i w przedziale wewnątrznaczyniowym, z tworzeniem fibryny w przestrzeniach powietrznych oraz zakrzepów w mikronaczyniach, co pogarsza uszkodzenie pęcherzyków i wymianę gazową.30

Koagulopatia ARDS charakteryzuje się mikroskrzepicą i tworzeniem agregatów płytkowo-leukocytarnych, które są prawdopodobnie kluczowymi procesami pośredniczącymi w uszkodzeniu płuc wywołanym sepsą.31

Immunotromboza, czyli interakcja między układem krzepnięcia a wrodzonym układem odpornościowym, jest nowym mechanizmem patogennym w ARDS. Neutrofile, makrofagi i inne efektory uczestniczą w odpowiedzi odpornościowej wrodzonej, a płytki krwi są głównymi komórkami zaangażowanymi w immunotrombozę.32

Fazy ARDS

ARDS tradycyjnie klasyfikuje się na trzy fazy, które opisują poziom zapalenia, gromadzenia się płynu i następujący proces naprawczy, któremu podlegają płuca w procesie gojenia:

Faza wysięgowa

Faza wysięgowa, odpowiadająca pierwszym 10 dniom infekcji, charakteryzuje się głównie tworzeniem błony szklistej w wyniku polimeryzacji fibryny płynu osocza, który przedostał się do przestrzeni śródmiąższowej/pęcherzykowej, uszkodzeniem bariery pęcherzykowo-włośniczkowej spowodowanym ekstrawazcją krwinek czerwonych oraz intensywnym naciekiem komórek zapalnych do przestrzeni wewnątrzpęcherzykowej.33 W tej fazie uszkodzenie płuc wywołane zapaleniem zwiększa przepuszczalność nabłonka, powodując rozlany obrzęk pęcherzyków.34

Faza proliferacyjna

W fazie proliferacyjnej nabłonek pęcherzykowy próbuje się zregenerować.35 Rozpoczyna się ona, gdy zmniejsza się poziom mediatorów zapalnych, następuje migracja fibroblastów do płuc, odkładanie się kolagenu i resorpcja płynu obrzękowego.36

Faza włóknienia

W fazie włóknistej niektóre odpowiedzi zapalne nie są rozwiązane i rozwijają się w przewlekłe zapalenie, prowadząc do włókniejącego zapalenia pęcherzyków z zmianami torbielowatymi przez infiltrujące makrofagi, fibrocyty, fibroblasty i miofibroblasty.37 Faza ta charakteryzuje się przebudową architektury płuc z włóknieniem i tworzeniem struktur plastra miodu, które upośledzają wymianę gazową.38

Rola makrofagów i neutrofili

Podczas przebiegu ARDS makrofagi pęcherzykowe (AM) istnieją w dynamicznej równowadze między prozapalnym stanem M1 a przeciwzapalnym stanem M2. Podtyp M1 jest indukowany przez prozapalne cytokiny Th1, takie jak IFN-γ oraz LPS. Następnie reaguje wydzielaniem IL-1, IL-12, TNF i indukowalnej syntazy tlenku azotu. Z kolei podtyp M2 jest indukowany przez cytokiny Th2, IL-4 i IL-13, i wydziela przeciwzapalne IL-10.39

Neutrofile odgrywają kluczową rolę w patogenezie ARDS, co sugerują badania płynu z płukania oskrzelowo-pęcherzykowego (BAL) i próbek biopsji płuc we wczesnym ARDS.40 Następnie rozpoczynają fagocytozę i degranulację elastazy neutrofilowej, mieloperoksydazy, reaktywnych form tlenu (ROS) i neutrofilowych pułapek zewnątrzkomórkowych (NETs), które pomagają w usuwaniu patogenów wirusowych, bakteryjnych lub grzybiczych.41

Neutrozy odnosi się do specyficznego dla neutrofili procesu śmierci komórkowej, w którym NETs są wykorzystywane do unieruchomienia i zabicia patogenów, przyspieszając jednocześnie własną śmierć. Śmiertelne dawki wirusa grypy A użyte u myszy wywołują rozległe tworzenie NETs w pęcherzykach płucnych, co prowadzi do niedrożności dróg oddechowych w oskrzelikach, rozszerzając się na uszkodzenie śródbłonka, a tym samym upośledzając wymianę gazową w naczyniach krwionośnych.42

Rola układu krzepnięcia

Dysregulacja układu krzepnięcia odgrywa istotną rolę w patogenezie ARDS. Aktywacja układu krzepnięcia z tworzeniem mikroskrzepów powodujących niedotlenienie tkanek przyczynia się do uszkodzenia naczyń płucnych w ARDS.43

W ostrej fazie ARDS uszkodzenie śródbłonka naczyniowego prowadzi do aktywacji układu krzepnięcia i tworzenia się zakrzepów w mikronaczyniach płucnych. Zakrzepy te przyczyniają się do zaburzeń perfuzji płuc i pogłębienia hipoksemii.44

W przypadku uszkodzenia płuc związanego z przetoczeniem krwi (TRALI) aktywowane płytki krwi indukują tworzenie się NETs, co sprzyja koagulacji i tworzeniu zakrzepów w płucach.45

Rola uszkodzenia płuc wywołanego przez respirator

Dowody z badań na zwierzętach sugerują, że rozwój ARDS może być promowany przez dodatnie ciśnienie w drogach oddechowych dostarczane do płuc przez wentylację mechaniczną. Jest to tzw. uszkodzenie płuc związane z respiratorem (VALI).46

ARDS wyraża się jako niejednorodny proces. Stosunkowo normalne pęcherzyki, które są bardziej podatne niż dotknięte pęcherzyki, mogą ulec nadmiernemu rozciągnięciu przez podawaną objętość oddechową, co znane jest jako wolutrauma, prowadząc do barotraumy (odma opłucnowa i powietrze śródmiąższowe).47

Oprócz mechanicznych skutków dla pęcherzyków płucnych, siły te sprzyjają wydzielaniu cytokin prozapalnych, co powoduje zaostrzenie stanu zapalnego i obrzęku płuc.48

Mechanizmy uszkodzenia biofizycznego związane z nadmiernym rozciągnięciem pęcherzyków odpowiadają za uszkodzenie płuc poprzez kilka efektów, w tym spadek napięcia powierzchniowego z powodu zmniejszenia właściwości surfaktantu, zwiększenie współczynnika filtracji i przepuszczalności białek w barierach śródbłonkowych i nabłonkowych, a także uszkodzenie rezydentnych komórek pęcherzykowych przez naprężenie rozciągające i naprężenie międzyfazowe.49

Uszkodzenie mechanotransdukcyjne

Termin mechanotransdukcja odnosi się do konwersji bodźców mechanicznych na odpowiedź biochemiczną, gdy nabłonek pęcherzykowy lub śródbłonek naczyniowy jest rozciągany podczas wentylacji mechanicznej.50 Wentylacja z dużą objętością oddechową powoduje przebudowę macierzy zewnątrzkomórkowej, na którą wpływa gradient ciśnienia w drogach oddechowych i gradient ciśnienia opłucnowego.51

Uszkodzenie mechanotransdukcyjne przyczynia się do rozwoju ARDS poprzez aktywację szlaków zapalnych, zwiększenie przepuszczalności śródbłonka i nabłonka oraz promowanie śmierci komórkowej.

Zaburzenia usuwania płynu pęcherzykowego

Większość pacjentów z ARDS ma upośledzoną zdolność do usuwania obrzęku płucnego, co wiąże się z wyższą śmiertelnością. Na resorpcję obrzęku pęcherzykowego u pacjentów z ARDS wpływa wiele mechanizmów, przy czym śmierć komórek nabłonka pęcherzykowego jest głównym mechanizmem.52

Sód wchodzi przez kanały szczytowe, zwłaszcza kanał sodowy nabłonkowy (ENaC), a następnie jest wydalany do śródmiąższu płuc przez Na/K-ATPazę umieszczoną po stronie podstawno-bocznej. Proces ten generuje lokalny gradient osmotyczny, który ułatwia reabsorpcję zawartości wody z płynu obrzękowego w przestrzeniach powietrznych płuc.53

Nadciśnienie płucne w ARDS

ARDS jest jednolicie związany z nadciśnieniem płucnym. Skurcz naczyń płucnych prawdopodobnie przyczynia się do niedopasowania wentylacji-perfuzji i jest jednym z mechanizmów hipoksemii w ARDS.54

Zatkane naczynia krwionośne również powodują nadciśnienie płucne, które jest pogorszone przez odpowiedź naczyń na hipoksję.55 Nadciśnienie płucne przyczynia się do prawokomorowej niewydolności serca i pogorszenia wymiany gazowej.

Patomechanizm hipoksemii w ARDS

ARDS powoduje znaczne zwiększenie przecieku wewnątrzpłucnego, prowadząc do ciężkiej hipoksemii.56 Hipoksemia wynika z kilku mechanizmów:

  • Przeciek prawo-lewy spowodowany wypełnieniem pęcherzyków płynem
  • Niedopasowanie wentylacji-perfuzji z powodu niejednorodnego uszkodzenia płuc
  • Zmniejszona powierzchnia wymiany gazowej z powodu zapadnięcia pęcherzyków
  • Zniszczenie architektury płuc przez włóknienie
  • Zaburzenia dyfuzji z powodu pogrubienia bariery pęcherzykowo-włośniczkowej

5758

Różnice w patogenezie zależne od etiologii

ARDS może być klasyfikowany jako pierwotny lub wtórny. Pierwotny ARDS opisuje uszkodzenie płuc z bezpośredniego uszkodzenia płuc (np. aspiracja). Wtórny ARDS opisuje uszkodzenie płuc jako część procesu ogólnoustrojowego (tj. płuco jest jednym z wielu narządów uszkodzonych przez ogólnoustrojową odpowiedź zapalną, taką jak sepsa).59

W bezpośrednim ARDS wywołanym sepsą, dysfunkcja płuc rozpoczyna się po zapaleniu płuc. Uwolnienie mediatorów prozapalnych, takich jak TNF, IL-1 i IL-6, prowadzi do utraty integralności bariery pęcherzykowo-włośniczkowej, rekrutacji neutrofili, dysfunkcji surfaktantu i obrzęku pęcherzyków.60

Pośredni ARDS wywołany sepsą powstaje w wyniku infekcji poza płucami. Mechanizm(y) leżący u podstaw rozwoju uszkodzenia płuc z infekcji w odległym miejscu są wieloczynnikowe i nie są dobrze poznane.61

Rola czynników genetycznych

Czynniki genetyczne gospodarza (pacjenta) i organizmów zakaźnych (czynniki wirulencji) prawdopodobnie odgrywają główną rolę zarówno w podatności, jak i ciężkości ALI/ARDS, ale nie mamy jeszcze odpowiedniego zrozumienia, jak wpływają one na przebieg ostrej niewydolności oddechowej w ALI/ARDS.62

Badania genów kandydujących wykazały związki między rozwojem ARDS u pacjentów z klinicznymi czynnikami ryzyka a polimorfizmami zaangażowanymi w zapalenie płuc, zapalenie ogólnoustrojowe lub aktywację śródbłonka.63

Podsumowanie patogenezy ARDS

Patogeneza ARDS jest złożona i wieloczynnikowa, obejmująca różne nakładające się i oddziałujące ze sobą szlaki związane z uszkodzeniem, zapaleniem i koagulacją, zarówno w płucach, jak i ogólnoustrojowo. Proces ten angażuje różnorodne komórki i mediatory, prowadząc ostatecznie do uszkodzenia bariery pęcherzykowo-włośniczkowej, obrzęku płuc, zaburzeń wymiany gazowej i hipoksemii.64

Zrozumienie złożonych mechanizmów patofizjologicznych ARDS jest kluczowe dla opracowania skutecznych strategii terapeutycznych ukierunkowanych na specyficzne szlaki patogenetyczne i zmniejszenia śmiertelności związanej z tym zespołem.

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  1. 11.04.2026
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Materiały źródłowe

  • #1 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    Acute Respiratory Distress Syndrome (ARDS) is a syndrome of acute respiratory failure caused by non-cardiogenic pulmonary edema. […] It is critical to study the molecular and physiologic mechanisms that cause ARDS in order to improve our understanding of this syndrome and reduce mortality. […] The goal of this review is to describe our current understanding of the pathogenesis and pathophysiology of ARDS. […] ARDS is a complex clinical syndrome with a heterogeneous clinical phenotype, which has made it more challenging to study. […] Nonetheless, since the first description of ARDS in 1967, advances in laboratory and clinical studies have yielded valuable insights into the mechanisms responsible for the pathogenesis and pathophysiology of this condition. […] When the lung is injured by infection, trauma, or inflammatory conditions, inflammatory pathways are activated.
  • #1
    https://insight.jci.org/articles/view/124061/figure/1
    Sepsis-induced acute respiratory distress syndrome (ARDS) has high morbidity and mortality and arises after lung infection or infection at extrapulmonary sites. An aberrant host response to infection leads to disruption of the pulmonary alveolar-capillary barrier, resulting in lung injury characterized by hypoxemia, inflammation, and noncardiogenic pulmonary edema. […] Here, we review the molecular underpinnings of sepsis-induced ARDS with a focus on relevant clinical and translational studies that point toward novel therapeutic strategies. […] Sepsis-induced ARDS arises from a lung infection (direct lung injury) or from an extrapulmonary source (indirect lung injury). The host response to the pathogen results in recruitment of inflammatory cells, release of proinflammatory cytokines, and other pathways of injury that damage the alveolar-capillary barrier. Loss of integrity of this barrier leads to influx of pulmonary edema fluid and lung injury.
  • #2 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    ARDS is associated with diffuse alveolar damage (DAD) and lung capillary endothelial injury. The early phase is described as being exudative, whereas the later phase is fibroproliferative in character. […] Early ARDS is characterized by an increase in the permeability of the alveolar-capillary barrier, leading to an influx of fluid into the alveoli. The alveolar-capillary barrier is formed by the microvascular endothelium and the epithelial lining of the alveoli. Hence, a variety of insults resulting in damage either to the vascular endothelium or to the alveolar epithelium could result in ARDS. […] The main site of injury may be focused on either the vascular endothelium (e.g., sepsis) or the alveolar epithelium (e.g., aspiration of gastric contents). Injury to the endothelium results in increased capillary permeability and the influx of protein-rich fluid into the alveolar space.
  • #2 The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3108259/
    The pathogenesis of ALI/ARDS can best be understood by focusing on (a) the factors that are responsible for the accumulation of protein-rich and neutrophilic pulmonary edema in the lung interstitium and in the distal air spaces of the lung and (b) the mechanisms that impair the removal of pulmonary edema fluid and inflammatory cells from the lung. The protein-rich edema fluid in ARDS is associated with large numbers of neutrophils; monocytes; denuded epithelial cells; and proinflammatory markers including cytokines, proteases, oxidants, and procoagulant factors. […] Lung vascular injury is the most important initial cause of ALI/ARDS. There is considerable evidence that an increase in lung vascular permeability occurs primarily at the level of lung microcirculation, which in turn results in the accumulation of protein-rich pulmonary edema, even in the presence of normal lung vascular pressure. Injury to the lung endothelium can occur by several mechanisms, although neutrophil-dependent lung injury is probably the best-documented pathway. In many experimental models, including acid-induced lung injury and transfusion-associated lung injury, neutrophils are a critical final pathway of lung injury. In the setting of both infectious and noninfectious lung injury, neutrophils accumulate in the lung microvasculature and become activated, leading to degranulation and the release of several toxic mediators, including proteases, reactive oxygen species, proinflammatory cytokines, and procoagulant molecules, which result in increased vascular permeability and a sustained loss of normal endothelial barrier function. The concept of neutrophil-dependent lung injury is important, but it also needs to be placed in the context of the vital role that neutrophils play in host defense, particularly against bacterial infection.
  • #3 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    In sum, the inflammatory-induced damage to lung endothelium results in increased capillary permeability, and thus leads to pulmonary edema formation. […] The alveolar epithelial barrier is similar to its endothelial counterpart, but has E-cadherin junctions instead of VE-cadherin junctions and it is substantially less permeable. […] Under pathologic conditions, neutrophil migration causes epithelial injury by disrupting intercellular junctions and causing apoptosis and denudation, ultimately resulting in increased epithelial permeability. […] Ultimately, resolution of ARDS requires repair of the endothelial and epithelial barriers to allow for effective reabsorption of the alveolar edema fluid, as well as removal of inflammatory cells and cytokines from the airspaces and the lung interstitium.
  • #4 ARDS – Symptoms and causes – Mayo Clinic
    https://www.mayoclinic.org/diseases-conditions/ards/symptoms-causes/syc-20355576
    Acute respiratory distress syndrome (ARDS) occurs when lung swelling causes fluid to build up in the tiny elastic air sacs in the lungs. These air sacs, called alveoli, have a protective membrane, but lung swelling damages that membrane. The fluid leaking into the air sacs keeps the lungs from filling with enough air. This means less oxygen reaches the bloodstream, so the body’s organs don’t get the oxygen they need to work properly. […] Causes of ARDS include: Sepsis. The most common cause of ARDS is sepsis, a serious and widespread infection of the bloodstream. […] Severe pneumonia. Severe cases of pneumonia usually affect all five lobes of the lungs. […] Coronavirus disease 2019 (COVID-19). People who have severe COVID-19 may get ARDS. Because COVID-19 mainly affects the respiratory system, it can cause lung injury and swelling that can lead to COVID-19-related ARDS.
  • #5 Acute Respiratory Distress Syndrome | Calgary Guide
    https://calgaryguide.ucalgary.ca/acute-respiratory-distress-syndrome-pathogenesis-and-clinical-findings/acute-respiratory-distress-syndrome/
    Acute respiratory distress syndrome (ARDS) is a clinical syndrome involving acute lung injury. It results in severe hypoxemia and bilateral airspace disease in the absence of elevated left-heart pressures. […] Direct Lung Injury Causes include pneumonia and pulmonary sepsis (community-acquired, hospital-acquired, aspiration, viral), drowning, and chemical pneumonitis from aspiration or direct inhalational injury. Indirect Lung Injury Causes include sepsis with a non-pulmonary source, trauma, severe burns, transfusion-related acute lung injury (TRALI) and pancreatitis. […] Lung Tissue Inflammation Exudative: Neutrophils migrate into the alveoli in response to inflammatory stimulus. […] Neutrophil-containing pulmonary exudate interferes with surfactant function. Neutrophil infiltration and proinflammatory cytokines lead to tissue edema, dysfunction and subsequent destruction of pulmonary epithelium. […] The body’s attempts to heal lung tissue result in deposition of hyaline membranes in the alveoli.
  • #6 Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS) | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-024-02678-5
    Acute respiratory distress syndrome (ARDS) is a common condition associated with critically ill patients, characterized by bilateral chest radiographical opacities with refractory hypoxemia due to noncardiogenic pulmonary edema. […] Comprehending the pathophysiology and the underlying molecular mechanisms of ARDS may thus be essential to developing effective therapeutic strategies and reducing mortality. […] We first describe the pathogenesis and pathophysiology of ARDS that involve dysregulated inflammation, alveolar-capillary barrier dysfunction, impaired alveolar fluid clearance and oxidative stress. […] The pathophysiology of ARDS is complex, involving dysregulation of inflammation, alveolar-capillary injury, impaired alveolar fluid clearance and oxidative stress. […] Regardless of the primary disease, the pathophysiologic manifestations of ARDS are very similar. Essentially, these syndromes reflect severe injury resulting in dysfunction of the alveolar-capillary barrier, impaired AFC, and oxidative injury due to unregulated acute inflammatory responses.
  • #7 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    Acute Respiratory Distress Syndrome (ARDS) is a syndrome of acute respiratory failure caused by non-cardiogenic pulmonary edema. […] It is critical to study the molecular and physiologic mechanisms that cause ARDS in order to improve our understanding of this syndrome and reduce mortality. […] The goal of this review is to describe our current understanding of the pathogenesis and pathophysiology of ARDS. […] ARDS is a complex clinical syndrome with a heterogeneous clinical phenotype, which has made it more challenging to study. […] Nonetheless, since the first description of ARDS in 1967, advances in laboratory and clinical studies have yielded valuable insights into the mechanisms responsible for the pathogenesis and pathophysiology of this condition. […] When the lung is injured by infection, trauma, or inflammatory conditions, inflammatory pathways are activated.
  • #8 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    The inflammatory response can aid in pathogen clearance, but excess inflammation can also contribute to alveolar damage specifically greater endothelial and epithelial permeability resulting in the accumulation of protein-rich alveolar edema fluid. […] In addition to excessive inflammation in ARDS, another central pathophysiologic derangement is the disruption of the lung microvascular barrier due to increased endothelial and epithelial permeability. […] During lung injury, increased concentrations of thrombin, tumor necrosis factor- (TNF-), vascular endothelial growth factor (VEGF), and leukocyte signals in the lungs destabilize the VE-cadherin bonds, resulting in increased endothelial permeability and the accumulation of alveolar fluid. […] The importance of VE-cadherin bonds has been confirmed in mouse models.
  • #9 Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-025-03137-5
    This review examines inflammatory markers, metabolic reprogramming, oxidative stress, and immune dysregulation, highlighting how these molecular and cellular processes converge to drive organ-level effects. It further elucidates how these interconnected pathways contribute to the onset, progression, and organ dysfunction associated with ARDS through intricate signaling networks. […] The cytokine storm is characterized by the release of numerous pro-inflammatory cytokines, including tumor necrosis factor- (TNF-), Interleukin-1 (IL-1), and IL-6. These cytokines activate signaling pathways such as nuclear factor-B (NF-B) and signal transducer and activator of transcription 3 (STAT3), increasing vascular permeability, disrupting the alveolar-capillary barrier, and resulting in pulmonary edema and severe hypoxemia.
  • #10 The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3108259/
    The pathogenesis of ALI/ARDS can best be understood by focusing on (a) the factors that are responsible for the accumulation of protein-rich and neutrophilic pulmonary edema in the lung interstitium and in the distal air spaces of the lung and (b) the mechanisms that impair the removal of pulmonary edema fluid and inflammatory cells from the lung. The protein-rich edema fluid in ARDS is associated with large numbers of neutrophils; monocytes; denuded epithelial cells; and proinflammatory markers including cytokines, proteases, oxidants, and procoagulant factors. […] Lung vascular injury is the most important initial cause of ALI/ARDS. There is considerable evidence that an increase in lung vascular permeability occurs primarily at the level of lung microcirculation, which in turn results in the accumulation of protein-rich pulmonary edema, even in the presence of normal lung vascular pressure. Injury to the lung endothelium can occur by several mechanisms, although neutrophil-dependent lung injury is probably the best-documented pathway. In many experimental models, including acid-induced lung injury and transfusion-associated lung injury, neutrophils are a critical final pathway of lung injury. In the setting of both infectious and noninfectious lung injury, neutrophils accumulate in the lung microvasculature and become activated, leading to degranulation and the release of several toxic mediators, including proteases, reactive oxygen species, proinflammatory cytokines, and procoagulant molecules, which result in increased vascular permeability and a sustained loss of normal endothelial barrier function. The concept of neutrophil-dependent lung injury is important, but it also needs to be placed in the context of the vital role that neutrophils play in host defense, particularly against bacterial infection.
  • #11 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. […] Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS. An imbalance of proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. […] Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI). […] ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than affected alveoli, may become overdistended by the delivered tidal volume, also known as volutrauma, resulting in barotrauma (pneumothorax and interstitial air).
  • #12 The Mechanics of ARDS
    https://www.medscape.org/viewarticle/514525
    ARDS is sometimes classified as primary or secondary. […] Primary ARDS describes lung injury from a direct lung insult (eg, aspiration). […] Secondary ARDS describes lung injury as part of a systemic process (ie, the lung is one of many organs injured by a systemic inflammatory response such as sepsis). […] This distinction may have important implications regarding pathogenesis and outcome, as described below. […] A number of cellular and biochemical mediators have been identified in ARDS, and a listing of some of the more well recognized ones include interleukins, tumor necrosis factor alpha, interferon gamma, cyclooxygenases, nitric oxide, neutrophil adhesion molecules, prostaglandins, leukotrienes, activated neutrophils, procoagulants, and platelet-activating factors. […] The relative importance of these mediators no doubt varies depending upon the etiology of the ARDS (including primary vs secondary ARDS).
  • #13 New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome
    https://www.mdpi.com/1422-0067/19/2/588
    Acute respiratory distress syndrome is an inflammatory disease characterized by dysfunction of pulmonary epithelial and capillary endothelial cells, infiltration of alveolar macrophages and neutrophils, cell apoptosis, necroptosis, NETosis, and fibrosis. […] The severe inflammatory responses induce the change of vascular permeability, leading to acute pulmonary edema. There are three major phases of ARDS: the exudative, proliferative, and fibroproliferative phases. […] In the exudative phase, the lung injury-induced inflammation cascade increases epithelial permeability, causing diffuse alveolar edema. […] Inflammatory cascades play key roles in processes that are closely involved in ARDS, such as cell apoptosis, proliferation, and migration. […] The immune response is triggered by activation of antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells, and endothelial cells.
  • #14 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    The inflammatory response can aid in pathogen clearance, but excess inflammation can also contribute to alveolar damage specifically greater endothelial and epithelial permeability resulting in the accumulation of protein-rich alveolar edema fluid. […] In addition to excessive inflammation in ARDS, another central pathophysiologic derangement is the disruption of the lung microvascular barrier due to increased endothelial and epithelial permeability. […] During lung injury, increased concentrations of thrombin, tumor necrosis factor- (TNF-), vascular endothelial growth factor (VEGF), and leukocyte signals in the lungs destabilize the VE-cadherin bonds, resulting in increased endothelial permeability and the accumulation of alveolar fluid. […] The importance of VE-cadherin bonds has been confirmed in mouse models.
  • #15 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    ARDS is associated with diffuse alveolar damage (DAD) and lung capillary endothelial injury. The early phase is described as being exudative, whereas the later phase is fibroproliferative in character. […] Early ARDS is characterized by an increase in the permeability of the alveolar-capillary barrier, leading to an influx of fluid into the alveoli. The alveolar-capillary barrier is formed by the microvascular endothelium and the epithelial lining of the alveoli. Hence, a variety of insults resulting in damage either to the vascular endothelium or to the alveolar epithelium could result in ARDS. […] The main site of injury may be focused on either the vascular endothelium (e.g., sepsis) or the alveolar epithelium (e.g., aspiration of gastric contents). Injury to the endothelium results in increased capillary permeability and the influx of protein-rich fluid into the alveolar space.
  • #16 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    The inflammatory response can aid in pathogen clearance, but excess inflammation can also contribute to alveolar damage specifically greater endothelial and epithelial permeability resulting in the accumulation of protein-rich alveolar edema fluid. […] In addition to excessive inflammation in ARDS, another central pathophysiologic derangement is the disruption of the lung microvascular barrier due to increased endothelial and epithelial permeability. […] During lung injury, increased concentrations of thrombin, tumor necrosis factor- (TNF-), vascular endothelial growth factor (VEGF), and leukocyte signals in the lungs destabilize the VE-cadherin bonds, resulting in increased endothelial permeability and the accumulation of alveolar fluid. […] The importance of VE-cadherin bonds has been confirmed in mouse models.
  • #17 The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3108259/
    The pathogenesis of ALI/ARDS can best be understood by focusing on (a) the factors that are responsible for the accumulation of protein-rich and neutrophilic pulmonary edema in the lung interstitium and in the distal air spaces of the lung and (b) the mechanisms that impair the removal of pulmonary edema fluid and inflammatory cells from the lung. The protein-rich edema fluid in ARDS is associated with large numbers of neutrophils; monocytes; denuded epithelial cells; and proinflammatory markers including cytokines, proteases, oxidants, and procoagulant factors. […] Lung vascular injury is the most important initial cause of ALI/ARDS. There is considerable evidence that an increase in lung vascular permeability occurs primarily at the level of lung microcirculation, which in turn results in the accumulation of protein-rich pulmonary edema, even in the presence of normal lung vascular pressure. Injury to the lung endothelium can occur by several mechanisms, although neutrophil-dependent lung injury is probably the best-documented pathway. In many experimental models, including acid-induced lung injury and transfusion-associated lung injury, neutrophils are a critical final pathway of lung injury. In the setting of both infectious and noninfectious lung injury, neutrophils accumulate in the lung microvasculature and become activated, leading to degranulation and the release of several toxic mediators, including proteases, reactive oxygen species, proinflammatory cytokines, and procoagulant molecules, which result in increased vascular permeability and a sustained loss of normal endothelial barrier function. The concept of neutrophil-dependent lung injury is important, but it also needs to be placed in the context of the vital role that neutrophils play in host defense, particularly against bacterial infection.
  • #18 The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3108259/
    Although lung endothelial injury is a prerequisite for the development of protein-rich pulmonary edema in ARDS, injury to the lung endothelium alone is usually not sufficient to cause the syndrome of ARDS in the absence of some degree of injury to the lung epithelium. For example, there is experimental evidence in large-animal models that moderately severe lung endothelial injury can occur without alveolar epithelial injury. In those studies, intravenous and/or intra-alveolar endotoxin produced sustained lung endothelial injury in sheep but did not cause the accumulation of alveolar edema, probably because the alveolar epithelium was morphologically and functionally intact. Alveolar edema developed in this model only when epithelial function was impaired by instillation of live bacteria. In addition to experimental evidence that epithelial injury is required for ARDS, the classic pathologic studies by Bachofen Weibel documented that patients with ARDS demonstrate both lung endothelial and alveolar epithelial injury.
  • #19 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    In sum, the inflammatory-induced damage to lung endothelium results in increased capillary permeability, and thus leads to pulmonary edema formation. […] The alveolar epithelial barrier is similar to its endothelial counterpart, but has E-cadherin junctions instead of VE-cadherin junctions and it is substantially less permeable. […] Under pathologic conditions, neutrophil migration causes epithelial injury by disrupting intercellular junctions and causing apoptosis and denudation, ultimately resulting in increased epithelial permeability. […] Ultimately, resolution of ARDS requires repair of the endothelial and epithelial barriers to allow for effective reabsorption of the alveolar edema fluid, as well as removal of inflammatory cells and cytokines from the airspaces and the lung interstitium.
  • #20 Pathogenesis of Acute Respiratory Distress Syndrome
    https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/
    In sum, the inflammatory-induced damage to lung endothelium results in increased capillary permeability, and thus leads to pulmonary edema formation. […] The alveolar epithelial barrier is similar to its endothelial counterpart, but has E-cadherin junctions instead of VE-cadherin junctions and it is substantially less permeable. […] Under pathologic conditions, neutrophil migration causes epithelial injury by disrupting intercellular junctions and causing apoptosis and denudation, ultimately resulting in increased epithelial permeability. […] Ultimately, resolution of ARDS requires repair of the endothelial and epithelial barriers to allow for effective reabsorption of the alveolar edema fluid, as well as removal of inflammatory cells and cytokines from the airspaces and the lung interstitium.
  • #21 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Injury to the alveolar lining cells also promotes pulmonary edema formation. Two types of alveolar epithelial cells exist. Type I cells, which make up 90% of the alveolar epithelium, are injured easily. Damage to type I cells allows both increased entry of fluid into the alveoli and decreased clearance of fluid from the alveolar space. […] Type II alveolar epithelial cells are relatively more resistant to injury. However, type II cells have several important functions, including the production of surfactant, ion transport, and proliferation and differentiation into type I cells after cellular injury. Damage to type II cells results in decreased production of surfactant with resultant decreased compliance and alveolar collapse. Interference with the normal repair processes in the lung may lead to the development of fibrosis.
  • #22 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Injury to the alveolar lining cells also promotes pulmonary edema formation. Two types of alveolar epithelial cells exist. Type I cells, which make up 90% of the alveolar epithelium, are injured easily. Damage to type I cells allows both increased entry of fluid into the alveoli and decreased clearance of fluid from the alveolar space. […] Type II alveolar epithelial cells are relatively more resistant to injury. However, type II cells have several important functions, including the production of surfactant, ion transport, and proliferation and differentiation into type I cells after cellular injury. Damage to type II cells results in decreased production of surfactant with resultant decreased compliance and alveolar collapse. Interference with the normal repair processes in the lung may lead to the development of fibrosis.
  • #23 Acute Respiratory Distress Syndrome – Pulmonary Pathophysiology for Pre-Clinical Students
    https://pressbooks.lib.vt.edu/pulmonarypathophysiology/chapter/acute-respiratory-distress-syndrome/
    Along with water cellular debris and proteins that accumulate in the airspace, providing an oncotic force to draw more water into the airspace, this cellular junk can settles and adds to the hyaline membrane to coat the inner surface of the alveolus, forming a barrier to gas exchange that will persist even after the edema has been resolved. […] The lack of gas exchange from affected areas produces a right-left shunt and hypoxemia will result. […] The loss of type II cells causes surfactant production to decline. […] The obstructed vasculature also produces pulmonary hypertension, which is exacerbated by the vasculatures response to the hypoxia. […] So now you should have a clear understanding that after an initial insult to the lung an exaggerated and perpetual inflammatory response leads to the destruction of the alveolar-capillary interface. The resulting edema and hyaline membrane formation produces severe hypoxemia and a critically ill patient.
  • #24 Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-025-03137-5
    In ARDS, the excessive release of ROS and RNS induces oxidative damage to cell membranes and proteins, compromising cellular function and integrity, which results in endothelial and epithelial barrier dysfunction, heightened vascular permeability, and, ultimately, pulmonary edema. […] Cell death is pivotal in the progression of ARDS, primarily mediated through apoptosis, necrosis, and pyroptosis. Apoptosis, a tightly regulated form of programmed cell death, is essential for eliminating damaged or infected cells, thereby preventing the spread of inflammation; however, excessive apoptosis can impair the lungs reparative capacity. […] In ARDS, EC injury and dysfunction are crucial in compromising the alveolar-capillary barrier, resulting in severe pathological consequences. […] Oxidative stress and cytokine storms induce apoptosis and necrosis in epithelial cells, compromising barrier function and resulting in fluid accumulation within the alveoli and the subsequent development of pulmonary edema.
  • #25 Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-025-03137-5
    In ARDS, the excessive release of ROS and RNS induces oxidative damage to cell membranes and proteins, compromising cellular function and integrity, which results in endothelial and epithelial barrier dysfunction, heightened vascular permeability, and, ultimately, pulmonary edema. […] Cell death is pivotal in the progression of ARDS, primarily mediated through apoptosis, necrosis, and pyroptosis. Apoptosis, a tightly regulated form of programmed cell death, is essential for eliminating damaged or infected cells, thereby preventing the spread of inflammation; however, excessive apoptosis can impair the lungs reparative capacity. […] In ARDS, EC injury and dysfunction are crucial in compromising the alveolar-capillary barrier, resulting in severe pathological consequences. […] Oxidative stress and cytokine storms induce apoptosis and necrosis in epithelial cells, compromising barrier function and resulting in fluid accumulation within the alveoli and the subsequent development of pulmonary edema.
  • #26 New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome
    https://www.mdpi.com/1422-0067/19/2/588
    Severe systemic inflammation-induced lung injury via pulmonary microvascular hyperpermeability is the first step in the development of ARDS. […] The release of VEGF, a permeability factor, also plays an important role in the pathogenesis of ARDS by promoting vascular permeability, exudation of protein-rich fluid, and migration of inflammatory cells. […] The ROS released downstream of inflammatory cytokines induce apoptosis and necroptosis in ARDS. […] In the fibroproliferative phase, some inflammatory responses are not resolved and develop into chronic inflammation, leading to fibrosing alveolitis with cystic changes by infiltrating macrophages, fibrocytes, fibroblasts, and myofibroblasts. […] The latest phase is characterized by remodeling of the lung architecture with fibrosis and honeycomb formation, which impair gas exchange.
  • #27 Pathophysiological mechanisms of ARDS: a narrative review from molecular to organ-level perspectives | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-025-03137-5
    In ARDS, the excessive release of ROS and RNS induces oxidative damage to cell membranes and proteins, compromising cellular function and integrity, which results in endothelial and epithelial barrier dysfunction, heightened vascular permeability, and, ultimately, pulmonary edema. […] Cell death is pivotal in the progression of ARDS, primarily mediated through apoptosis, necrosis, and pyroptosis. Apoptosis, a tightly regulated form of programmed cell death, is essential for eliminating damaged or infected cells, thereby preventing the spread of inflammation; however, excessive apoptosis can impair the lungs reparative capacity. […] In ARDS, EC injury and dysfunction are crucial in compromising the alveolar-capillary barrier, resulting in severe pathological consequences. […] Oxidative stress and cytokine storms induce apoptosis and necrosis in epithelial cells, compromising barrier function and resulting in fluid accumulation within the alveoli and the subsequent development of pulmonary edema.
  • #28 Signaling pathways and potential therapeutic targets in acute respiratory distress syndrome (ARDS) | Respiratory Research | Full Text
    https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-024-02678-5
    Inflammatory injury caused by immune response inevitably aggravates the direct damage to AECs, including cell death and intercellular junction disruption, leading to increased alveolar epithelial permeability. […] The failure to absorb alveolar edema fluid significantly contributes to increased mortality in ARDS. […] Oxidative stress, resulting from the production of reactive oxygen species (ROS), plays an important role in ARDS progression and lung injury. […] The excessive generation of ROS is well-established to be causative in the pathogenesis and progression of ARDS. […] The current understanding is that the protective mechanism involves the nuclear factor erythroid 2-related factor (Nrf2) pathway against oxidative stress.
  • #29 Protective mechanism of sulforaphane in Nrf2 and anti-lung injury in ARDS rabbits
    https://www.spandidos-publications.com/10.3892/etm.2018.6036
    The effect of sulforaphane on nuclear factor erythroid 2-related factor 2 (Nrf2) and its protective mechanism for lung injury in rabbits with acute respiratory distress syndrome (ARDS) were investigated. […] Acute lung injury (ALI), also known as acute respiratory distress syndrome (ARDS), is a common critical disease caused by ALI. […] The occurrence of inflammation begins from the inflammatory cell exudate and immune cell-mediated breakdown of alveolar epithelial interstitial barrier, making plasma and proteins, flood the pulmonary interstitium and air space in turn. […] Currently, ARDS is recognized as a neutrophil-driven disease; moreover, it has been increasingly recognized that innate cells (including macrophages and platelets) and adaptive immune system are involved in the incidence of ARDS.
  • #30 New insights in ARDS pathogenesis
    https://www.signavitae.com/articles/10.22514/sv.2022.058
    Inflammation and activated endothelial cells trigger coagulation cascades and platelets that generate a procoagulant state in both the airspace and the intravascular compartment with the formation of fibrin in airspaces and thrombi in the microvasculature that aggravate alveolar injury and gas exchange. […] The crosstalk between epithelial/endothelial cells, platelets, and immune cells is mediated by EVs, whose role in the pathogenesis of ARDS is not known. […] Finally, the interaction of the lung with other organs has become an important determinant in the development and resolution of ARDS. […] Understanding the pathophysiological mechanisms involved in ARDS is crucial to developing new therapeutic strategies.
  • #31
    https://insight.jci.org/articles/view/124061
    The coagulopathy of sepsis has been reviewed in detail previously. […] Microvascular thrombosis and formation of platelet-leukocyte aggregates are likely key processes mediating sepsis-induced lung injury. […] Apoptosis-mediated depletion of CD4+ T cells and B cells has been proposed to lead to sepsis-induced immunoparalysis. […] The process of resolution and repair described above is orchestrated by different cell types and several classes of master regulators. […] These pathways lead to the formation of focal adhesion kinases and the assembly of intercellular junctions. […] The matrix also plays a key role in orchestrating the proliferation of various structural cells to restore normal lung architecture. […] The process of resolution and repair described above is orchestrated by different cell types and several classes of master regulators.
  • #32 Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies | Signal Transduction and Targeted Therapy
    https://www.nature.com/articles/s41392-025-02127-9
    Several key signaling pathways are involved in immunoinflammation during ARDS, including macrophages and endothelial cells. IL33-STAT3-MMP2/9 is reported to play an important role in macrophage polarization from anti-inflammatory phenotype (M2) to proinflammatory phenotype (M1), thus inducing lipopolysaccharide (LPS)-induced ALI and pulmonary inflammation. Macrophage polarization further leads to endothelial injury. […] Immunothrombosis, the interaction between the coagulation system and the innate immune system after infection, is an emerging pathogenic mechanism in ARDS, especially in CARDS. Neutrophils, macrophages, and other effectors are involved in the innate immune response, and platelets are the primary cells involved in immunothrombosis and complement signaling. The complement system participates in the immunothrombosis process in CARDS. Complement activation has been reported to be associated with enhanced thrombotic activity, and blockade of C5aR1 can alleviate platelet-mediated thrombogenicity in a neutrophil extracellular trap (NET)-dependent manner in ARDS. Increased NET formation is associated with microthrombus and platelet accumulation in the pulmonary circulation, indicating that NETs promote immunothrombosis in ARDS. Additionally, endothelial activation plays a pivotal role in immunothrombosis and aberrant coagulation since elevated levels of endothelium-derived glycoproteins have been detected in ARDS patients with blood type A and are associated with an increased risk of disseminated intravascular coagulation.
  • #33 COVID-19 induced ARDS: immunopathology and therapeutics
    https://www.explorationpub.com/Journals/ei/Article/1003101
    The immune system plays a major role in the pathogenesis of COVID-19-induced ARDS and can be targeted for successful therapy. […] Lung vascular injury is the major cause of ARDS. […] The first or exudative phase, which corresponds to the first 10 days of viral infection, is primarily characterized by the formation of a hyaline membrane as a result of the fibrin polymerization of plasma liquid that leaked into the interstitial/alveolar space, alveolar-capillary barrier injury caused by red blood cell extravasation, and intense inflammatory cell infiltration into the intra-alveolar space. […] In the course of the infection, SARS-CoV-2 triggers both innate and adaptive immune responses, this response may also lead to extremely severe inflammatory reactions causing damage to tissues which can be on the systemic and local levels, such as lung diseases.
  • #34 New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome
    https://www.mdpi.com/1422-0067/19/2/588
    Acute respiratory distress syndrome is an inflammatory disease characterized by dysfunction of pulmonary epithelial and capillary endothelial cells, infiltration of alveolar macrophages and neutrophils, cell apoptosis, necroptosis, NETosis, and fibrosis. […] The severe inflammatory responses induce the change of vascular permeability, leading to acute pulmonary edema. There are three major phases of ARDS: the exudative, proliferative, and fibroproliferative phases. […] In the exudative phase, the lung injury-induced inflammation cascade increases epithelial permeability, causing diffuse alveolar edema. […] Inflammatory cascades play key roles in processes that are closely involved in ARDS, such as cell apoptosis, proliferation, and migration. […] The immune response is triggered by activation of antigen-presenting cells (APCs), such as monocytes, macrophages, dendritic cells, and endothelial cells.
  • #35 Acute Respiratory Distress Syndrome ARDS CXR findings | Calgary Guide
    https://calgaryguide.ucalgary.ca/acute-respiratory-distress-syndrome-ards-cxr-findings/acute-respiratory-distress-syndrome-ards-cxr-findings/
    Degradation of alveolar-capillary barrier […] Proliferative phase […] Alveolar epithelium attempts to recover […] Chronic phase Can either resolve or progress to fibrotic thickening and scaring of alveoli […] Leakage of fluid from capillaries into alveoli and lung interstitium […] Pulmonary fibrosis (scarring)
  • #36 Pathophysiology of ARDS | SpringerLink
    https://link.springer.com/chapter/10.1007/978-88-470-0765-9_7
    Acute respiratory distress syndrome (ARDS) is a quite common disease, with an annual incidence ranging from 1.5 to 8.3 cases for every 100000 patients and a mortality of 3050%. In 1994, the American European Consensus Conference defined ARDS as: an acute and persistent lung disease characterized by an arterial hypoxemia (PaO2/FiO2200 mmHg), resistant to oxygen therapy and bilateral infiltrates on chest X ray. In general, ARDS has two different pathogeneses: a direct pulmonary insult to the lung cell or an indirect extrapulmonary insult resulting in a systemic inflammatory response. ARDS is a progressive disease, with different stages, different mediators, and both inflammatory and anti-inflammatory activity (cellular and humoural). At the beginning of the inflammatory response, changes occur in the alveolar capillary barrier, including the formation of a protein-rich fluid, alteration of surfactant and migration into the lung of neutrophils, lymphocytes and macrophages. Plasma factors, such as complement, and mediators generated by the cells, such as cytokines, oxidants and leucotrienes, are secreted inappropriately and at high levels. Resolution of the disease starts with a decrease in the levels of inflammatory mediators, the migration of fibroblasts into the lung, collagen deposition and the re-absorption of oedema fluid.
  • #37 New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome
    https://www.mdpi.com/1422-0067/19/2/588
    Severe systemic inflammation-induced lung injury via pulmonary microvascular hyperpermeability is the first step in the development of ARDS. […] The release of VEGF, a permeability factor, also plays an important role in the pathogenesis of ARDS by promoting vascular permeability, exudation of protein-rich fluid, and migration of inflammatory cells. […] The ROS released downstream of inflammatory cytokines induce apoptosis and necroptosis in ARDS. […] In the fibroproliferative phase, some inflammatory responses are not resolved and develop into chronic inflammation, leading to fibrosing alveolitis with cystic changes by infiltrating macrophages, fibrocytes, fibroblasts, and myofibroblasts. […] The latest phase is characterized by remodeling of the lung architecture with fibrosis and honeycomb formation, which impair gas exchange.
  • #38 New Insights into the Immune Molecular Regulation of the Pathogenesis of Acute Respiratory Distress Syndrome
    https://www.mdpi.com/1422-0067/19/2/588
    Severe systemic inflammation-induced lung injury via pulmonary microvascular hyperpermeability is the first step in the development of ARDS. […] The release of VEGF, a permeability factor, also plays an important role in the pathogenesis of ARDS by promoting vascular permeability, exudation of protein-rich fluid, and migration of inflammatory cells. […] The ROS released downstream of inflammatory cytokines induce apoptosis and necroptosis in ARDS. […] In the fibroproliferative phase, some inflammatory responses are not resolved and develop into chronic inflammation, leading to fibrosing alveolitis with cystic changes by infiltrating macrophages, fibrocytes, fibroblasts, and myofibroblasts. […] The latest phase is characterized by remodeling of the lung architecture with fibrosis and honeycomb formation, which impair gas exchange.
  • #39 Insights into the immuno-pathogenesis of acute respiratory distress syndrome
    https://atm.amegroups.org/article/view/29655/25958
    The pathogenesis of ARDS is multi-factorial and involves diverse immune cells of both the innate and adaptive immune system that mediate the propagation of lung injury triggered by these insults. […] During the disease course of ARDS, AMs exist in a dynamic balance between pro-inflammatory M1 and anti-inflammatory M2 polarized states. […] Clinical studies of patients with direct and indirect ARDS reaffirmed that a state of sustained monocyte influx positively correlates with severity of respiratory failure as indicated by the higher oxygenation index. […] The M1 subtype is induced by proinflammatory TH1 cytokines, such as IFN- as well as LPS. It then responds with the secretion of IL-1, IL-12, TNF and inducible nitric oxide synthase. In contrast, the M2 subtype is induced by TH2 cytokines IL-4 and IL-13 and secretes anti-inflammatory IL-10.
  • #40 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. […] Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS. An imbalance of proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. […] Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI). […] ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than affected alveoli, may become overdistended by the delivered tidal volume, also known as volutrauma, resulting in barotrauma (pneumothorax and interstitial air).
  • #41 Insights into the immuno-pathogenesis of acute respiratory distress syndrome
    https://atm.amegroups.org/article/view/29655/25958
    Neutrophils subsequently begin phagocytosis and degranulation of neutrophil elastase, myeloperoxidase, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) which assist in clearance of viral, bacterial or fungal pathogens. Netosis refers to a neutrophil specific cell death process whereby NETS are deployed to immobilize and kill pathogens while precipitating its own death. […] Lethal doses of Influenza A used in mice incites extensive NETs formation within the alveoli resulting in airway obstruction within bronchioles, extending to endothelial damage thus impairing gas exchange across blood vessels. […] In transfusion-related acute lung injury (TRALI), activated platelets induce NETs formation promoting coagulation and thrombi formation in the lungs. […] The immunomodulatory effects of Treg cells and M2 polarized AMs, is asserted as one of the main mechanisms for the beneficial effects of cell-based therapy on ARDS, specifically mesenchymal stem cell (MSC) therapy.
  • #42 Insights into the immuno-pathogenesis of acute respiratory distress syndrome
    https://atm.amegroups.org/article/view/29655/25958
    Neutrophils subsequently begin phagocytosis and degranulation of neutrophil elastase, myeloperoxidase, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) which assist in clearance of viral, bacterial or fungal pathogens. Netosis refers to a neutrophil specific cell death process whereby NETS are deployed to immobilize and kill pathogens while precipitating its own death. […] Lethal doses of Influenza A used in mice incites extensive NETs formation within the alveoli resulting in airway obstruction within bronchioles, extending to endothelial damage thus impairing gas exchange across blood vessels. […] In transfusion-related acute lung injury (TRALI), activated platelets induce NETs formation promoting coagulation and thrombi formation in the lungs. […] The immunomodulatory effects of Treg cells and M2 polarized AMs, is asserted as one of the main mechanisms for the beneficial effects of cell-based therapy on ARDS, specifically mesenchymal stem cell (MSC) therapy.
  • #43 Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome | eLife
    https://elifesciences.org/articles/77405
    The development of PARDS in response to a severe physiologic insult is thought to reflect epithelial lung injury, systemic inflammation, and activation of the vascular endothelium. Candidate gene studies, therefore, have largely focused on genetic polymorphisms related to these processes, including surfactant protein function, pulmonary inflammation, systemic inflammation, and endothelial activation. […] Candidate genes associated with systemic inflammation have been of long-standing interest in PARDS. Systemic inflammation often accompanies pulmonary inflammation, and systemic inflammatory processes such as sepsis are risk factors for PARDS. Tumor necrosis factor- (TNF-), encoded by the TNFA gene, is a pleiotropic cytokine and a primary mediator of systemic inflammation. […] The activation of coagulation system with microthrombi causing tissue hypoxia contributes to pulmonary vascular injury in PARDS. The endothelial protein C receptor (EPCR, encoded by the PROCR gene) plays a cytoprotective role in sepsis by activating protein C (APC) and mediating APC effects.
  • #44 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with resultant worsening inflammation and pulmonary edema. […] ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. […] Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. […] ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. […] The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are filled with mesenchymal cells and new blood vessels.
  • #45 Insights into the immuno-pathogenesis of acute respiratory distress syndrome
    https://atm.amegroups.org/article/view/29655/25958
    Neutrophils subsequently begin phagocytosis and degranulation of neutrophil elastase, myeloperoxidase, reactive oxygen species (ROS) and neutrophil extracellular traps (NETs) which assist in clearance of viral, bacterial or fungal pathogens. Netosis refers to a neutrophil specific cell death process whereby NETS are deployed to immobilize and kill pathogens while precipitating its own death. […] Lethal doses of Influenza A used in mice incites extensive NETs formation within the alveoli resulting in airway obstruction within bronchioles, extending to endothelial damage thus impairing gas exchange across blood vessels. […] In transfusion-related acute lung injury (TRALI), activated platelets induce NETs formation promoting coagulation and thrombi formation in the lungs. […] The immunomodulatory effects of Treg cells and M2 polarized AMs, is asserted as one of the main mechanisms for the beneficial effects of cell-based therapy on ARDS, specifically mesenchymal stem cell (MSC) therapy.
  • #46 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. […] Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS. An imbalance of proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. […] Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI). […] ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than affected alveoli, may become overdistended by the delivered tidal volume, also known as volutrauma, resulting in barotrauma (pneumothorax and interstitial air).
  • #47 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    Neutrophils are thought to play a key role in the pathogenesis of ARDS, as suggested by studies of bronchoalveolar lavage (BAL) and lung biopsy specimens in early ARDS. […] Cytokines (tumor necrosis factor [TNF], leukotrienes, macrophage inhibitory factor, and numerous others), along with platelet sequestration and activation, are also important in the development of ARDS. An imbalance of proinflammatory and anti-inflammatory cytokines is thought to occur after an inciting event, such as sepsis. […] Evidence from animal studies suggests that the development of ARDS may be promoted by the positive airway pressure delivered to the lung by mechanical ventilation. This is termed ventilator-associated lung injury (VALI). […] ARDS expresses itself as an inhomogeneous process. Relatively normal alveoli, which are more compliant than affected alveoli, may become overdistended by the delivered tidal volume, also known as volutrauma, resulting in barotrauma (pneumothorax and interstitial air).
  • #48 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with resultant worsening inflammation and pulmonary edema. […] ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. […] Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. […] ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. […] The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are filled with mesenchymal cells and new blood vessels.
  • #49 Ventilator-Induced Lung Injury (VILI) in Acute Respiratory Distress Syndrome (ARDS): Volutrauma and Molecular Effects
    https://openrespiratorymedicinejournal.com/VOLUME/9/PAGE/112/
    The second phenomenon unfolds in dependent lung regions (RD), which are exposed to significant stress when the airway and alveoli open on inspiration and collapse on expiration tidal recruitment. […] The volutrauma effects over the lung parenchyma can be evaluated at different spatial scales, in this sense the response of its resident cells to the deforming stress take importance in order to provide the biological basis of lung protective care. […] Mechanisms of biophysical injury associated with alveolar overdistension are responsible for lung injury through several effects including a decline in the surface tension due to reduction in surfactant properties, an increase of filtration coefficient and protein permeability in the endothelial and epithelial barriers, as well as wounding of alveolar resident cells by tensile and interfacial stress.
  • #50 Ventilator-Induced Lung Injury (VILI) in Acute Respiratory Distress Syndrome (ARDS): Volutrauma and Molecular Effects
    https://openrespiratorymedicinejournal.com/VOLUME/9/PAGE/112/
    The term mechanotransduction is referred to the conversion of mechanical stimuli to a biochemical response when alveolar epithelium or vascular endothelium is stretched during mechanical ventilation. […] High-VT ventilation causes ECM remodeling, influenced by the airway pressure gradient and the pleural pressure gradient. […] The relationship between pathophysiological events presented in VILI and mechanotransduction are shown in Fig. (1).
  • #51 Ventilator-Induced Lung Injury (VILI) in Acute Respiratory Distress Syndrome (ARDS): Volutrauma and Molecular Effects
    https://openrespiratorymedicinejournal.com/VOLUME/9/PAGE/112/
    The term mechanotransduction is referred to the conversion of mechanical stimuli to a biochemical response when alveolar epithelium or vascular endothelium is stretched during mechanical ventilation. […] High-VT ventilation causes ECM remodeling, influenced by the airway pressure gradient and the pleural pressure gradient. […] The relationship between pathophysiological events presented in VILI and mechanotransduction are shown in Fig. (1).
  • #52 Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies | Signal Transduction and Targeted Therapy
    https://www.nature.com/articles/s41392-025-02127-9
    After the pulmonary capillary endothelium was destroyed, proteinaceous fluid and white blood cells flew into the alveolus, causing diffuse lung inflammation and coagulation. Red blood cells (RBCs) also crossed the pulmonary capillary endothelium and could be found in the alveoli of patients with ARDS. Lysis of RBCs within the intravascular and alveolar spaces results in the release of cell-free hemoglobin (CFH), which was harmful. The mechanism of CFH injury in acute respiratory distress syndrome may be specifically mediated through targeted cell surface receptor binding on the alveolar epithelium, as an in vitro study demonstrated that supplementation with antioxidants or iron chelators did not alter the effect of methemoglobin. […] Most patients with ARDS had impaired ability to clear pulmonary edema, which was associated with a higher mortality rate. Several mechanisms influence the resolution of alveolar edema in patients with ARDS, with the death of alveolar epithelial cells being the primary mechanism. Sodium enters through apical channels, especially the epithelial sodium channel (ENaC), and is then expelled into the lung interstitium by the Na/K-ATPase situated on the basolateral side. This process generates a localized osmotic gradient that facilitates the reabsorption of the water content from the edema fluid within the airspaces of the lungs. […] In the pathophysiology of ARDS, macrophages, neutrophils, alveolar epithelial cells, endothelial cells, etc., influence the pathological progression of ARDS through various mechanisms, mainly including cell death, cellular senescence, and cellular dysfunction.
  • #53 Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies | Signal Transduction and Targeted Therapy
    https://www.nature.com/articles/s41392-025-02127-9
    After the pulmonary capillary endothelium was destroyed, proteinaceous fluid and white blood cells flew into the alveolus, causing diffuse lung inflammation and coagulation. Red blood cells (RBCs) also crossed the pulmonary capillary endothelium and could be found in the alveoli of patients with ARDS. Lysis of RBCs within the intravascular and alveolar spaces results in the release of cell-free hemoglobin (CFH), which was harmful. The mechanism of CFH injury in acute respiratory distress syndrome may be specifically mediated through targeted cell surface receptor binding on the alveolar epithelium, as an in vitro study demonstrated that supplementation with antioxidants or iron chelators did not alter the effect of methemoglobin. […] Most patients with ARDS had impaired ability to clear pulmonary edema, which was associated with a higher mortality rate. Several mechanisms influence the resolution of alveolar edema in patients with ARDS, with the death of alveolar epithelial cells being the primary mechanism. Sodium enters through apical channels, especially the epithelial sodium channel (ENaC), and is then expelled into the lung interstitium by the Na/K-ATPase situated on the basolateral side. This process generates a localized osmotic gradient that facilitates the reabsorption of the water content from the edema fluid within the airspaces of the lungs. […] In the pathophysiology of ARDS, macrophages, neutrophils, alveolar epithelial cells, endothelial cells, etc., influence the pathological progression of ARDS through various mechanisms, mainly including cell death, cellular senescence, and cellular dysfunction.
  • #54 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with resultant worsening inflammation and pulmonary edema. […] ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. […] Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. […] ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. […] The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are filled with mesenchymal cells and new blood vessels.
  • #55 Acute Respiratory Distress Syndrome – Pulmonary Pathophysiology for Pre-Clinical Students
    https://pressbooks.lib.vt.edu/pulmonarypathophysiology/chapter/acute-respiratory-distress-syndrome/
    Along with water cellular debris and proteins that accumulate in the airspace, providing an oncotic force to draw more water into the airspace, this cellular junk can settles and adds to the hyaline membrane to coat the inner surface of the alveolus, forming a barrier to gas exchange that will persist even after the edema has been resolved. […] The lack of gas exchange from affected areas produces a right-left shunt and hypoxemia will result. […] The loss of type II cells causes surfactant production to decline. […] The obstructed vasculature also produces pulmonary hypertension, which is exacerbated by the vasculatures response to the hypoxia. […] So now you should have a clear understanding that after an initial insult to the lung an exaggerated and perpetual inflammatory response leads to the destruction of the alveolar-capillary interface. The resulting edema and hyaline membrane formation produces severe hypoxemia and a critically ill patient.
  • #56 Acute Respiratory Distress Syndrome (ARDS): Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/165139-overview
    In addition to the mechanical effects on alveoli, these forces promote the secretion of proinflammatory cytokines with resultant worsening inflammation and pulmonary edema. […] ARDS causes a marked increase in intrapulmonary shunting, leading to severe hypoxemia. […] Theoretically, high FiO2 levels may cause DAD via oxygen free radical and related oxidative stresses, collectively called oxygen toxicity. […] ARDS is uniformly associated with pulmonary hypertension. Pulmonary artery vasoconstriction likely contributes to ventilation-perfusion mismatch and is one of the mechanisms of hypoxemia in ARDS. […] The acute phase of ARDS usually resolves completely. Less commonly, residual pulmonary fibrosis occurs, in which the alveolar spaces are filled with mesenchymal cells and new blood vessels.
  • #57 Pediatric Acute Respiratory Distress Syndrome: Practice Essentials, Background, Pathophysiology
    https://emedicine.medscape.com/article/803573-overview
    The net effect is impairment in oxygenation. A widened interstitial space between the alveolus and the vascular endothelium decreases oxygen-diffusing capacity. Hypoxia arises as a result of the change described above. […] Iatrogenic factors may further complicate the clinical picture. Oxygen toxicity, volutrauma, barotraumas, and fluid overload can further aggravate the lung injury and worsening lung compliance and oxygenation. […] Resolution of ARDS is a very complex and active process. Alveolar edema resolves by active transport mechanism, where water follows sodium and chloride ions. Termination of inflammation involves anti-inflammatory mediators like IL-10, tissue growth factor (TGF) and pre resolution mediators like polyunsaturated fatty acids, including lipoxins, resolvins, and protectins. […] If the injury is severe, disorganized and insufficient, epithelial repair may result into fibrosis and loss of lung function.
  • #58 Acute respiratory distress syndrome (ARDS) : Virtual Library
    https://resources.wfsahq.org/atotw/acute-respiratory-distress-syndrome-ards/
    First described in 1967, ARDS is a process of hypoxaemic respiratory failure associated with non-cardiogenic pulmonary oedema. It is the result of diffuse inflammatory damage to the alveoli and pulmonary capillaries from a range of local or systemic insults. ARDS is often associated with multiple organ dysfunction and carries a high mortality and financial cost. […] In those that do there are said to be three overlapping phases: an inflammatory phase, a proliferative phase and a fibrotic phase caused by the subsequent reparative response. Patients with ARDS/ALI do not have to progress through all three phases as resolution can occur at any point. However, the severest form of ARDS will progress to the fibrotic phase. […] Neutrophils accumulate in the capillaries, interstitial tissue and airspaces, and cause cell damage through the production of free radicals, inflammatory mediators and proteases. However neutrophils are not the only cell type involved as ARDS does occur in neutropenic patients. Cytokines (most importantly TNF-, IL-1 IL-6 and IL-8) are also released by endothelial and immune cells and promote similar microvascular damage. The result is leakage of fluid and plasma proteins into the alveoli and interstitial tissues (non-cardiogenic pulmonary oedema), while at the same time the plasma proteins denature alveolar surfactant causing alveolar collapse. This creates hypoxia as the fluid-filled alveoli shunt blood. Shunt is created when areas of lung receive a blood supply but are unable to oxygenate it (in this case by creating a diffusion barrier.)
  • #59 The Mechanics of ARDS
    https://www.medscape.org/viewarticle/514525
    ARDS is sometimes classified as primary or secondary. […] Primary ARDS describes lung injury from a direct lung insult (eg, aspiration). […] Secondary ARDS describes lung injury as part of a systemic process (ie, the lung is one of many organs injured by a systemic inflammatory response such as sepsis). […] This distinction may have important implications regarding pathogenesis and outcome, as described below. […] A number of cellular and biochemical mediators have been identified in ARDS, and a listing of some of the more well recognized ones include interleukins, tumor necrosis factor alpha, interferon gamma, cyclooxygenases, nitric oxide, neutrophil adhesion molecules, prostaglandins, leukotrienes, activated neutrophils, procoagulants, and platelet-activating factors. […] The relative importance of these mediators no doubt varies depending upon the etiology of the ARDS (including primary vs secondary ARDS).
  • #60
    https://insight.jci.org/articles/view/124061
    In direct sepsis-induced ARDS, lung dysfunction begins following pneumonia. […] Release of proinflammatory mediators, such as TNF, IL-1, and IL-6, lead to loss of alveolar-capillary barrier integrity, neutrophil recruitment, surfactant dysfunction, and alveolar edema. […] Indirect sepsis-induced ARDS arises from an infection outside the lung. The mechanism(s) underlying the development of lung injury from an infection at a distant site are multifactorial and not well understood. […] Damage to the alveolar-capillary barrier can be further fueled by alterations to microvascular endothelial cells and through formation of microthrombi. […] In preclinical models of sepsis-induced ARDS, mechanical ventilation produces synergistic injury compared with sepsis or VILI alone. […] Sepsis-induced ARDS is initiated by an inflammatory host response to a microbial pathogen.
  • #61
    https://insight.jci.org/articles/view/124061
    In direct sepsis-induced ARDS, lung dysfunction begins following pneumonia. […] Release of proinflammatory mediators, such as TNF, IL-1, and IL-6, lead to loss of alveolar-capillary barrier integrity, neutrophil recruitment, surfactant dysfunction, and alveolar edema. […] Indirect sepsis-induced ARDS arises from an infection outside the lung. The mechanism(s) underlying the development of lung injury from an infection at a distant site are multifactorial and not well understood. […] Damage to the alveolar-capillary barrier can be further fueled by alterations to microvascular endothelial cells and through formation of microthrombi. […] In preclinical models of sepsis-induced ARDS, mechanical ventilation produces synergistic injury compared with sepsis or VILI alone. […] Sepsis-induced ARDS is initiated by an inflammatory host response to a microbial pathogen.
  • #62 The Acute Respiratory Distress Syndrome: Pathogenesis and Treatment
    https://pmc.ncbi.nlm.nih.gov/articles/PMC3108259/
    Thus, ventilation with higher tidal volumes and elevated airway pressures causes more lung inflammation and probably results in direct mechanical injury to the lung epithelium and endothelium as well. Follow-up human studies have demonstrated that patients who are ventilated with lower tidal volumes and lower airway pressures had a reduction both in plasma levels of interleukin (IL)-8, IL-6, and soluble TNF receptor 1 and in the number of neutrophils and inflammatory markers in the air spaces of the lung. Furthermore, levels of the alveolar epithelial type II cell marker SP-D and the receptor for advanced glycation end products (RAGE) were also reduced in patients who were ventilated with a lower tidal volume. […] Although there has been considerable progress in understanding the pathogenesis of ALI/ARDS, there are several important gaps in our knowledge. First, the mechanisms that lead to alveolar epithelial injury, including gap formation and apoptosis and necrosis of type I and type II cells, are not well understood. Second, the mechanisms that contribute to restoration of a normal alveolar epithelium require more study. Third, we need to understand the extent to which the proinflammatory and procoagulant pathways are protective in lung injury because they play a necessary role in host defense against invading bacteria, viruses, and fungi. Fourth, the genetic factors of the host (the patient) and the infecting organisms (virulence factors) probably play a major role in both the susceptibility and the severity of ALI/ARDS, but we do not yet have an adequate understanding of how they influence the course of acute respiratory failure in ALI/ARDS. Fifth, there are probably important environmental factors that contribute to the development and severity of ALI/ARDS that require more study, including the potential influence of exposure to cigarette smoke.
  • #63 Evolution of multiple omics approaches to define pathophysiology of pediatric acute respiratory distress syndrome | eLife
    https://elifesciences.org/articles/77405
    As a whole, candidate gene studies have demonstrated associations between the development of ARDS in patients with clinical risk factors and polymorphisms implicated in pulmonary inflammation, systemic inflammation, or endothelial activation. […] In summary, protein biomarker studies in PARDS have been numerous and are highly feasible. They have described a pattern of epithelial and endothelial perturbations as well as systemic inflammation, which mirrors the findings of protein biomarker studied first conducted in adults with ARDS. […] These recent investigations represent an exciting development because they elucidate some of the pathobiological changes associated with lower respiratory tract infection that make a host vulnerable to ARDS.
  • #64 Advances in acute respiratory distress syndrome: focusing on heterogeneity, pathophysiology, and therapeutic strategies | Signal Transduction and Targeted Therapy
    https://www.nature.com/articles/s41392-025-02127-9
    The pathophysiology of ARDS is complex, and the mechanism includes the activation and dysregulation of multiple overlapping and interacting pathways associated with injury, inflammation, and coagulation, both in the lungs and systemically; this process involves a variety of cells. The pathological changes that occur in ARDS include alveolar epithelial injury, pulmonary endothelial injury, pulmonary macrophage injury, and pulmonary fibroblast injury, which are all observed in animal models of ALI/ARDS. Oxidative stress, inflammation, apoptosis, and barrier breakdown are observed in alveolar epithelial cells and pulmonary endothelial cells in mice with ALI, with increased levels of alveolar injury markers and endothelial injury markers. […] ARDS is a syndrome that can impact pulmonary tissue as well as extrapulmonary tissues. Several systemic pathological changes, such as immune dysfunction, inflammatory responses, and abnormal coagulation, have been reported to occur during ARDS. Herein, we focus on the interactions between immune dysfunction and inflammation and the interactions between coagulation disorders and inflammation in the context of lung thrombosis, which are classified as immunoinflammation and immunothrombosis, respectively.

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