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. […] When the lung is injured by infection, trauma, or inflammatory conditions, inflammatory pathways are activated. […] 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.

• #2 Pathophysiology of Acute Respiratory Distress Syndrome and COVID-19 Lung Injury

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8162817/

  The pathophysiology of acute respiratory distress syndrome (ARDS) is marked by inflammation-mediated disruptions in alveolar-capillary permeability, edema formation, reduced alveolar clearance and collapse/derecruitment, reduced compliance, increased pulmonary vascular resistance, and resulting gas exchange abnormalities due to shunting and ventilation-perfusion mismatch. […] Acute respiratory distress syndrome (ARDS) is a complex syndrome of acute lung injury leading to noncardiogenic pulmonary edema from many causes that is heterogenous in its clinical presentation and associated with a 40% mortality rate. Extensive work since its initial description in 1967 has elucidated biological pathways causing the many physiologic changes of alveolar collapse/derecruitment, reduced lung compliance, greater pulmonary vascular resistance, and gas exchange impairment that can be compounded by patient’s own ventilatory response or assisted ventilatory support, due to regional heterogeneity of the underlying lung injury.

• #2 Pathogenesis of Acute Respiratory Distress Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/

  The importance of VE-cadherin bonds has been confirmed in mouse models. […] 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. […] In ARDS, the osmotic gradient is disrupted and AFC is reduced, further compounding the decreased capacity to remove edema fluid from the distal airspaces of the lung. […] In the uninjured lung, vectorial ion transport across the intact alveolar epithelial layer creates an osmotic gradient that drives fluid from the alveoli into the lung interstitium.

• #2 Pathophysiology of Acute Respiratory Distress Syndrome and COVID-19 Lung Injury

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8162817/

  It is useful to briefly review the pathogenesis of lung injury and repair in ARDS to understand its effects on physiology. Injury begins with activation of alveolar macrophages by microbial or cell injury products, which are locally derived in primary lung injury (pulmonary ARDS) or systemically derived (extrapulmonary ARDS). Cytokine/chemokine release by macrophages recruits and activates circulating neutrophils, which release myriad inflammatory molecules. Although assisting with pathogen killing, they also injure the normally tight alveolar endothelialepithelial barrier consisting of adherent cell-cell contacts and glycocalyx linings. […] As a result of loss of the normal low permeability characteristics, the alveolar space fills with an inflammatory cell-rich proteinaceous edema fluid (exudative phase of ARDS), a prime determinant of lung injury severity, alveolar collapse, and derecruitment.

• #2 Pathophysiology of Acute Respiratory Distress Syndrome and COVID-19 Lung Injury

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8162817/

  The consequences of the above changes to alveolar structure and histology are gas exchange impairment, increased work breathing, and dyspnea leading to respiratory failure. Alveolar flooding along with pulmonary vascular injury generates the entire spectrum of VA/Q abnormalities from areas with reduced ventilation-to-perfusion (VA/Q) ratios and intrapulmonary shunting to high VA/Q ratios and dead space. […] Given little or no ventilation to these areas, arterial hypoxemia is insensitive to global increases in ventilation. Increased Fio2 can improve oxygenation in low VA/Q regions, though not in shunts. […] The use of the BohrEnghoff equation to estimate dead space with values as high as 75% overestimates the magnitude of physiologic dead space in ARDS occurring from vascular obstruction and vasoconstriction.

• #2 Pathophysiology of Acute Respiratory Distress Syndrome and COVID-19 Lung Injury

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8162817/

  Nonetheless, a rising CO2 dead space may be associated with increased vascular resistance and right heart dysfunction indicative of vascular obstruction. […] The ability of the lung to maintain a highly compliant and dry alveolar air space for efficient gas exchange at a low work of breathing cost depends upon a number of factors, including surfactant production and active vectorial alveolar epithelial sodium and water transport from the alveolar space into the interstitium for reuptake into the blood or lymphatic transport. […] In ARDS, the surfactant is inactivated, and alveolar epithelial injury leads to loss of fluid reabsorption. […] The role of lung injury while on positive pressure ventilation is the best studied. Positive pressure ventilation along with PEEP reduces the work of breathing and prevents atelectasis of nearly collapsed lung units to improve gas exchange.

• #3 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

  Acute respiratory distress syndrome (ARDS) remains a life-threatening pulmonary condition with persistently high mortality rates despite significant advancements in supportive care. Its complex pathophysiology involves an intricate interplay of molecular and cellular processes, including cytokine storms, oxidative stress, programmed cell death, and disruption of the alveolar-capillary barrier. These mechanisms drive localized lung injury and contribute to systemic inflammatory response syndrome and multiple organ dysfunction syndrome. […] The pathogenesis of ARDS is highly complex, with dysregulated inflammation and epithelial barrier dysfunction at the core of its pathology. Therefore, a thorough and systematic examination of the pathophysiological mechanisms underlying ARDS is crucial for enhancing clinical outcomes.

• #3 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.

• #3 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.

• #3 Pathogenesis of Acute Respiratory Distress Syndrome

  https://pmc.ncbi.nlm.nih.gov/articles/PMC7060969/

  However, in the setting of ARDS, the capacity to remove alveolar edema fluid is reduced, which is termed impaired alveolar fluid clearance (AFC). […] 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. […] The study of novel therapeutic strategies, including cell-based MSC treatment, has further refined our understanding of ARDS pathophysiology, and may offer promising new treatment options for this condition.

• #4 Acute Respiratory Distress Syndrome – Pulmonary Pathophysiology for Pre-Clinical Students

  https://pressbooks.lib.vt.edu/pulmonarypathophysiology/chapter/acute-respiratory-distress-syndrome/

  Learning objectives Describe the pathogenesis and pathophysiology of acute respiratory distress syndrome (ARDS). […] So let us look at the pathophysiological processes underlying what is now universally known as ARDS. […] Regardless of the insults route or indeed form, the ensuing pathological events are similar and lead to the same alteration of the lungs. What is initiated is a defensive inflammatory response, and what results is vascular endothelial and alveolar epithelial damage and a leaky alveolar capillary membrane. […] The injury causes release of inflammatory cytokines, and tumor necrosis factor, interleukin (IL)-1, IL-6, and IL-8 have been shown to be particularly involved in ARDS. […] The neutrophils, however, begin to release toxic mediators, but rather than resolve the underlying, initial problem, the released reactive oxygen species and proteases disrupt the capillary endothelium and the alveolar epithelium.

• #5 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.)

• #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

  The pathophysiology of ARDS is complex, involving dysregulation of inflammation, alveolar-capillary injury, impaired alveolar fluid clearance and oxidative stress. […] 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. […] 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.

• #7 Pathophysiology and Treatment of Acute Respiratory Distress Syndrome | Encyclopedia MDPI

  https://encyclopedia.pub/entry/52639

  Specifically, activated neutrophils contribute to tissue damage by releasing cytotoxic agents, including granular enzymes, pro-inflammatory cytokines, bioactive lipids, and reactive oxygen species (ROS). […] The acute phase, referred to as the exudative stage, typically spans from hours to the first week after the injury onset. During this stage, a cascading inflammatory response is activated, leading to an influx of neutrophils, a phenomenon that results in the disruption of the alveolar epithelial and endothelial barriers, and consequently, protein-rich edema in the interstitium and alveolar spaces. […] To gain a deeper understanding of the intricate pathophysiology of ARDS and to develop novel therapeutic strategies, researchers have extensively utilized controlled experimental models to mimic clinical syndromes.

• #8 Insights into the immuno-pathogenesis of acute respiratory distress syndrome

  https://atm.amegroups.org/article/view/29655/25958

  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. […] 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.

• #9 Acute Respiratory Distress Syndrome (ARDS) | Concise Medical Knowledge

  https://www.lecturio.com/concepts/acute-respiratory-distress-syndrome/

  Acute respiratory distress syndrome is characterized by the sudden onset of hypoxemia and bilateral pulmonary edema. […] The underlying mechanism and histologic correlate is diffuse alveolar damage (DAD). […] Diffuse alveolar damage involves damage to the endothelial and alveolar epithelial cells and is associated with inflammation and the development of hyaline membranes lining the inner alveolar walls. […] Acute respiratory distress syndrome begins with an initial injury to the pneumocytes and pulmonary endothelium, which starts a chain reaction of increasing inflammation and pulmonary damage that can have an uneven/patchy distribution. […] The exudative phase starts within 6-72 hours after an eliciting risk factor, progresses rapidly, and lasts about 7 days. […] Destruction of alveolar epithelial cells and capillary endothelial cells produces numerous effects: damage to the alveolar capillary membrane, release of pro-inflammatory cytokines, inactivation of the surfactant, and formation of hyaline membranes that line the inner alveolar walls.

• #9 Acute Respiratory Distress Syndrome (ARDS) | Concise Medical Knowledge

  https://www.lecturio.com/concepts/acute-respiratory-distress-syndrome/

  Loss of surfactant also results in a large increase in the surface tension of alveoli, leading to alveolar instability and atelectasis. […] The effects on lung function include stiff lungs, reduced lung compliance, reduced diffusing capacity, shortness of breath, and hypoxemia. […] Acute respiratory distress syndrome is clinically diagnosed using the Berlin diagnostic criteria. […] The diagnosis requires the presence of a known clinical risk factor (e.g., pneumonia, trauma, sepsis), or hydrostatic edema is ruled out via imaging when a risk factor is absent. […] Acute respiratory distress syndrome is a serious condition that is usually associated with high mortality and morbidity. […] Direct lung injuries result in twice the number of mortalities compared to indirect causes of lung injury.

• #10 Acute Respiratory Distress Syndrome (ARDS) – Creative Med Doses

  https://creativemeddoses.com/topics-list/acute-respiratory-distress-syndrome-ards/

  Acute Respiratory Distress Syndrome has three phases: exudative, proliferative, and fibrotic. All of them have characteristic clinical and pathologic features. […] In this phase, alveolar capillary endothelial cells and type I pneumocytes (alveolar epithelial cells) are injured, and tight alveolar barrier is damaged giving away the entry to fluid and macromolecules. The protein rich edema fluid accumulates in the interstitial and alveolar spaces. Pro-inflammatory cytokines are increased in this acute phase, leading to the recruitment of leukocytes (especially neutrophils) into the pulmonary interstitium and alveoli. There is plasma proteins aggregation in air spaces with cellular debris and dysfunctional pulmonary surfactant to form hyaline membrane whorls. Alveolar edema predominantly involves dependent portions of the lung with diminished aeration. Collapse of large sections of dependent lung can contribute to decreased lung compliance. It causes intrapulmonary shunting and hypoxemia develop and the work of breathing increases, leading to dyspnea.

• #10 Acute Respiratory Distress Syndrome (ARDS) – Creative Med Doses

  https://creativemeddoses.com/topics-list/acute-respiratory-distress-syndrome-ards/

  This phase of ARDS usually lasts from day 7 to day 21. Most patients recover rapidly and are liberated from mechanical ventilation during this phase. Despite this improvement, many patients still experience dyspnea, tachypnea, and hypoxemia. Histologically, the first signs of resolution are often evident in this phase, with the initiation of lung repair, the organization of alveolar exudates, and a shift from neutrophil- to lymphocyte-predominant pulmonary infiltrates. […] Most patients with ARDS recover lung function within 34 weeks, very few progresses into fibrotic phase that may require long-term support on mechanical ventilators and/or supplemental oxygen. There is extensive alveolar-duct and interstitial fibrosis. Marked disruption of acinar architecture leads to emphysema-like changes, with large bullae. Intimal fibroproliferation in the pulmonary microcirculation causes progressive vascular occlusion and pulmonary hypertension. The physiologic consequences include an increased risk of pneumothorax, reductions in lung compliance, and increased pulmonary dead space.

• #11 Acute Respiratory Distress Syndrome: Diagnosis and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2020/0615/p730.html

  Acute respiratory distress syndrome (ARDS) is noncardiogenic pulmonary edema that manifests as rapidly progressive dyspnea, tachypnea, and hypoxemia. […] ARDS is thought to occur when a pulmonary or extrapulmonary insult causes the release of inflammatory mediators, promoting inflammatory cell accumulation in the alveoli and microcirculation of the lung. Inflammatory cells damage the vascular endothelium and alveolar epithelium, leading to pulmonary edema, hyaline membrane formation, decreased lung compliance, and decreased gas exchange. […] ARDS progresses through several phases after a direct pulmonary or indirect extrapulmonary insult. In the exudative phase, which may last seven to 10 days, alveolar macrophages secrete mediators that lead to accumulation of inflammatory cells in the lung. This accumulation, in combination with neutrophil and alveolar epithelial cell activation, leads to tissue injury. Inflammatory cells migrate across the vascular endothelial and alveolar epithelial surfaces and proinflammatory mediators and chemokines are released, leading to pathologic vascular permeability, gaps in the alveolar epithelial barrier, and necrosis of types I and II alveolar cells.

• #11 Acute Respiratory Distress Syndrome: Diagnosis and Management | AAFP

  https://www.aafp.org/pubs/afp/issues/2020/0615/p730.html

  The proliferative phase begins the process of lung repair over the next two to three weeks. Anti-inflammatory cytokines deactivate inciting neutrophils, which then undergo apoptosis and phagocytosis. Type II alveolar cells proliferate and differentiate into type I cells, reestablishing the integrity of the epithelial lining. […] The fibrotic phase, which does not occur in all patients, is characterized by ongoing inflammation, extensive basement membrane damage, persistent edema, intra-alveolar and interstitial fibrosis, and microvascular damage.

• #12 Acute Respiratory Distress Syndrome; A Review of Recent Updates and a Glance into the Future

  https://www.mdpi.com/2075-4418/13/9/1528

  The proliferative phase takes place over the following days to weeks and is the body’s way of “recalibrating” itself to repair. Anti-inflammatory cytokines facilitate neutrophil apoptosis and clearance, macrophages clear cellular debris via phagocytosis, type 2 pneumocytes begin to proliferate and differentiate into type 1 pneumocytes, the integrity of the epithelium is reestablished, and fluid begins to be cleared via active transport and diffusion. […] The fibrotic stage of ARDS and what leads to it taking place in only some patients has yet to be understood. […] Understanding the heterogeneity of ARDS has been the subject of research. This “phenotyping” and “sub-phenotyping” of ARDS was demonstrated in randomized controlled trials by the National Institutes of Health–National Heart, Lung, and Blood Institute (NIH–NHLBI) ARDS Network, where they showed that one phenotype had worse clinical outcomes associated with more severe inflammation, shock, and metabolic acidosis when compared to the other phenotype they had in their study.

• #12 Acute Respiratory Distress Syndrome; A Review of Recent Updates and a Glance into the Future

  https://www.mdpi.com/2075-4418/13/9/1528

  Better understanding of a variety of factors that could be behind these phenotypes is a part of the “precision medicine” approach to ARDS, with the fields of metabolomics and epigenetics playing crucial roles. […] The pathogenesis of ARDS is characterized by neutrophil-dependent lung injury. Neutrophil accumulation results in endothelial injury coupled with alveolar epithelial damage leading to alveolar edema.

• #13 The maximum expression of hypoxia and hypoventilation: Acute respiratory distress syndrome | Revista Médica del Hospital General de México

  https://www.elsevier.es/en-revista-revista-medica-del-hospital-general-325-avance-resumen-the-maximum-expression-hypoxia-hypoventilation-S0185106317300240

  The third and final phase is the fibrotic phase, which occurs inconsistently and consists of failure to remove collagen and alveolar remodelling, which was established at the start of the injury, combined with the development of cystic changes, thereby limiting functional recovery. […] Diffuse alveolar damage is the pathognomonic pathological finding in ARDS. It is defined by the presence of hyaline membrane and may be detected through lung biopsy and autopsy. However, it is non-specific and may occur in the absence of acute respiratory distress syndrome, just as ARDS may occur in the absence of diffuse alveolar damage.

• #14 Pathophysiology of acute respiratory distress syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Pathophysiology_of_acute_respiratory_distress_syndrome

  Fluid accumulation in the lungs and decreased surfactant production by type II pneumocytes may cause whole air sacs to collapse or to completely fill with fluid. This loss of aeration contributes further to the right-to-left shunt in ARDS. […] In ARDS, a lung right-to-left shunting occurs within the lungs since some blood from the right side of the heart will enter capillaries which cannot exchange gas with damaged air sacs that are full of fluid and debris from ARDS. […] As the loss of aeration and the underlying disease progress, the end tidal volume grows to a level incompatible with life. Thus, mechanical ventilation is initiated to relieve muscles responsible for supporting breathing (respiratory muscles) of their work and to protect the affected person’s airway. However, mechanical ventilation may constitute a risk factor for the development or the worsening of ARDS. […] This form of stress is thought to be applied by the transpulmonary pressure (gradient) generated by the ventilator or, better, its cyclical variations.

• #15 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 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. Additionally, hemoglobin increased leukocyte-endothelial adhesion and activated lung microvascular endothelial cells through TLR4 signaling under inflammatory and hemolytic conditions. […] 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.

• #15 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 activation of the adaptive immune system in ARDS involves T lymphocytes, B lymphocytes, antigen-presenting cells (APCs), and several influential factors, such as complement. […] 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.

• #15 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 impairment or degeneration of tight junction proteins is thought to accelerate endothelial barrier disruption and play a vital role in hyperpermeability during ARDS. Plasma from severe COVID-19 ARDS patients could impair the endothelial barrier integrity of primary human pulmonary microvascular endothelial cells in vitro, as indicated by decreased endothelial resistance measured by electrical cell impedance sensing (ECIS), transendothelial electrical resistance (TEER) and loss of occludin. […] 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.

• #15 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

  Immunoinflammation, the initial immunological response that leads to inflammation and initiates a vicious cycle of immune responses and inflammation, is closely associated with the molecular pathogenesis of ARDS. In ARDS caused by infection, immune responses, including innate and adaptive immune responses, are first activated by pathogens. However, in noninfective ARDS, alveolar epithelial cell injury, pulmonary endothelial activation, and alveolar macrophage responses can recruit neutrophils and natural killer (NK) cells as well as monocytes, such as macrophages and dendritic cells, from the circulation, thus initiating the immune response during ARDS. An active immune response ultimately leads to immune disorders in ARDS patients, further promoting the inflammatory response through similar effector cells in both immune and inflammatory aetiologies.

• #15 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

  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. […] Due to systemic and pulmonary immunoinflammatory and immunothrombosis during ARDS, as well as subsequent disruption of the alveolar-capillary barrier, various cellular pathological changes, including various types of cell death, cellular senescence, and cellular dysfunction, have been demonstrated to occur in damaged pulmonary tissue. The potential underlying mechanism involves disruption of intracellular functions, such as excessive ROS accumulation, endoplasmic dysfunction, and mitochondrial dysfunction.

• #15 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

  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. […] ARDS exhibits clinical heterogeneity. ARDS can be divided into subphenotypes based on clinical features, causes of lung injury, effective biomarkers, or clinical and biological variables. This heterogeneity may explain the lack of benefit observed in most randomized controlled trials (RCTs) evaluating various treatment strategies. […] Accurate subphenotypic classification of ARDS will improve clinical outcomes. […] The response of subphenotypes to mechanical ventilation was tested in several clinical trials. Patients randomized to the high- vs. low-PEEP strategy had mortality rates of 24% and 16% for the hypoinflammatory subphenotype, respectively, compared with 42% and 51%, respectively, for the hyperinflammatory subphenotype.

• #15 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

  In summary, the pathogenesis of ARDS involves complex interactions between various cellular and molecular mechanisms, leading to significant clinical heterogeneity and varying responses to treatment. Further research is essential to translate these findings into effective clinical interventions and personalized treatment approaches for ARDS, ultimately leading to better outcomes for patients suffering from ARDS.

• #16 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.

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