Materiały źródłowe

• #1 Pulmonary arterial hypertension: pathogenesis and clinical management – PubMed

  https://pubmed.ncbi.nlm.nih.gov/29540357/

  Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis. Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. PAH is a panvasculopathy, meaning that all layers of the vascular wall are involved. PAH is also reflective of gene environment interactions and has important genetic and epigenetic mechanisms. The net effect of these abnormalities is a state of vasoconstriction, inflammation, thrombosis with a hyperproliferative, apoptosis resistant PASMC population, which promotes vasoconstriction and vascular obstruction, and excessive fibrosis, which reduces vascular compliance. These vascular changes ultimately increase right ventricular (RV) afterload and impair RV-pulmonary artery coupling, leading to RV failure. Mitochondrial fragmentation in pulmonary arterial hypertension (PAH) reflects increase in mitotic fission in PAH that results from increased expression of activated dynamin related protein 1 and reduced expression of fission mediator mitofusin 2.

• #2

  https://smw.ch/index.php/smw/article/view/2086

  Elevation of the mean pulmonary arterial pressure to 25 mm Hg within the low-pressure system of the pulmonary circulation is defined as pulmonary hypertension. […] Many of these conditions, however, result in a final common pathway of pathogenesis. This pathway is characterised by the triad of excessive vasoconstriction, microthrombosis and remodelling of pulmonary arteries. Remodelling is arguably the most important factor: its complex pathogenesis is not completely understood and no specific treatment directly targets vascular remodelling. This article aims to review the current understanding of the pathogenesis of pulmonary hypertension and to give insights in future developments in this evolving field.

• #3 Pathophysiology and new advances in pulmonary hypertension | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000137

  Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions. […] The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterised by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle. […] The pathogenesis of pulmonary arterial hypertension is driven by the crosstalk between multiple cell types in the lung, including vascular cells, immune cells, and circulating cells. Pulmonary artery endothelial cells, pulmonary artery smooth muscle cells, and pulmonary artery fibroblasts are the major cells involved in the pathogenesis.

• #4 Pathophysiology and new advances in pulmonary hypertension | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000137

  Endothelial dysfunction results in decreased production of vasodilating agents (eg, nitric oxide and prostacyclin) and increased synthesis of procontractile mediators (eg, endothelin 1). […] Abnormalities in the signalling pathways of transforming growth factor β and bone morphogenetic receptor protein 2 are key drivers of the development of pulmonary arterial hypertension (and, to some degree, also pulmonary hypertension). […] Inflammation is a phenomenon commonly found in various types of pulmonary hypertension. […] Dysfunctional angiogenesis is a major contributor to the development of pulmonary arterial hypertension. […] Abnormal metabolic remodelling has emerged as a major driver of the pathogenesis of pulmonary arterial hypertension, and a key principle in pulmonary arterial hypertension relates to the shift from oxidative phosphorylation to glycolysis, known as the Warburg effect.

• #5 Pulmonary Arterial Hypertension: Practice Essentials, Pathophysiology, Etiology

  https://emedicine.medscape.com/article/303098-overview

  Increased pulmonary vascular resistance is the main pathogenic mechanism in pulmonary arterial hypertension (PAH). This is typically due to vasoconstriction, remodeling, and thrombosis of the small pulmonary arteries and arterioles. […] On the molecular level, this is related to endothelial dysfunction, which leads to disorganized endothelial cell proliferation, decreased production of vasodilators such as prostacyclin and nitric oxide, and overexpression of vasoconstrictors like endothelin. These pathophysiologic mechanisms are particularly important as they guide the therapeutic targets of pharmacotherapies for advanced PAH disease.

• #6 Pulmonary arterial hypertension: pathogenesis and clinical management | The BMJ

  https://www.bmj.com/content/360/bmj.j5492

  Pulmonary hypertension is defined as a resting mean pulmonary artery pressure of 25 mm Hg or above. This review deals with pulmonary arterial hypertension (PAH), a type of pulmonary hypertension that primarily affects the pulmonary vasculature. In PAH, the pulmonary vasculature is dynamically obstructed by vasoconstriction, structurally obstructed by adverse vascular remodeling, and pathologically non-compliant as a result of vascular fibrosis and stiffening. Many cell types are abnormal in PAH, including vascular cells (endothelial cells, smooth muscle cells, and fibroblasts) and inflammatory cells. Progress has been made in identifying the causes of PAH and approving new drug therapies. A cancer-like increase in cell proliferation and resistance to apoptosis reflects acquired abnormalities of mitochondrial metabolism and dynamics. Mutations in the type II bone morphogenetic protein receptor (BMPR2) gene dramatically increase the risk of developing heritable PAH. Epigenetic dysregulation of DNA methylation, histone acetylation, and microRNAs also contributes to disease pathogenesis. Aberrant bone morphogenetic protein signaling and epigenetic dysregulation in PAH promote cell proliferation in part through induction of a Warburg mitochondrial-metabolic state of uncoupled glycolysis.

• #7 New Mutations and Pathogenesis of Pulmonary Hypertension: Progress and Puzzles in Disease Pathogenesis – Williams College

  http://librarysearch.williams.edu/discovery/fulldisplay/cdi_unpaywall_primary_10_1161_circresaha_122_320084/01WIL_INST:01WIL_SPECIAL

  Pulmonary arterial hypertension (PAH) is a complex multifactorial disease with poor prognosis characterized by functional and structural alterations of the pulmonary circulation causing marked increase in pulmonary vascular resistance, ultimately leading to right heart failure and death. […] Mutations in the gene encoding BMPRII-a receptor for the TGF-β (transforming growth factor-beta) superfamily—account for over 70% of families with PAH and ≈20% of sporadic cases. […] This review will consider how these newly discovered PAH genes could help to provide a better understanding of the molecular and cellular bases of the maintenance of the pulmonary vascular integrity, as well as their role in the PAH pathogenesis underlying occlusion of arterioles in the lung. […] We will also discuss how insights into the genetic contributions of these new PAH-related genes may open up new therapeutic targets for this, currently incurable, cardiopulmonary disorder.

• #8 Pulmonary Hypertension – Pulmonary Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/pulmonary-disorders/pulmonary-hypertension/pulmonary-hypertension

  Thrombotic coagulopathy due to platelet dysfunction, increased activity of plasminogen activator inhibitor type 1 and fibrinopeptide A, and decreased tissue plasminogen activator activity may also contribute. […] Mutations in the BMPR2 gene account for most cases of hereditary PAH and also occurs in idiopathic PAH. Aberrant BMPR2 signaling disturbs the TGF-/BMP balance, favoring a pro-proliferative and anti-apoptotic response in pulmonary artery smooth muscle and endothelial cells. […] Increased pulmonary venous pressure is typically caused by disorders that affect the left side of the heart and raise left chamber pressures, which ultimately lead to elevated pressure in the pulmonary veins. […] Elevated pulmonary venous pressures can cause acute damage to the alveolar-capillary wall and subsequent edema.

• #8 Pulmonary Hypertension – Pulmonary Disorders – MSD Manual Professional Edition

  https://www.msdmanuals.com/professional/pulmonary-disorders/pulmonary-hypertension/pulmonary-hypertension

  Pathophysiologic mechanisms that cause pulmonary hypertension include […] Increased pulmonary vascular resistance is caused by […] Pathologic vasoconstriction […] Obliteration of the pulmonary vascular bed […] Pulmonary hypertension is characterized by variable and sometimes pathologic vasoconstriction and by endothelial and smooth muscle proliferation, hypertrophy, and chronic inflammation, resulting in vascular wall remodeling. Vasoconstriction is thought to be due in part to enhanced activity of thromboxane and endothelin-1 (both vasoconstrictors) and reduced activity of prostacyclin and nitric oxide (both vasodilators). […] The increased pulmonary vascular pressure that results from vascular obstruction further injures the endothelium. Injury activates coagulation at the intimal surface, which may worsen the hypertension.

• #9 Pulmonary arterial hypertension: pathogenesis and clinical management | The BMJ

  https://www.bmj.com/content/360/bmj.j5492

  Complex changes in cytokines (interleukins and tumor necrosis factor), cellular immunity (T lymphocytes, natural killer cells, macrophages), and autoantibodies suggest that PAH is, in part, an autoimmune, inflammatory disease. Obstructive pulmonary vascular remodeling in PAH increases right ventricular afterload causing right ventricular hypertrophy. In some patients, maladaptive changes in the right ventricle, including ischemia and fibrosis, reduce right ventricular function and cause right ventricular failure. […] However, these vasodilators do not target key features of PAH pathogenesis and have not been shown to reduce mortality, which remains about 50% at five years.

• #10 Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-024-02772-8

  Histopathological evidence has suggested that perivascular infiltration of inflammatory cells is common in PH and precedes structural remodelling in vessels. […] The activation of macrophages in the hypoxia-induced experimental PH model has been reported to be related to alterations in several signalling pathways and cytokines, such as hypoxia-inducible factor 1 (HIF-1), IL-6, NF-B, HIMF and IL-6. […] Macrophages are involved in many typical hallmarks of PH, such as smooth muscle cell proliferation and fibroblast activation, which are essential for PH development. […] M1 and M2 macrophages are commonly treated as signs of different stages in PH pathogenesis. M1 macrophages promote inflammation, while M2 macrophages have anti-inflammatory functions and regulate tissue repair. […] Macrophages are now recognized as candidate therapeutic targets for PH treatment due to their unique role in PH pathogenesis, suggesting a new strategy for preventing and even reversing PH progression.

• #11 Pulmonary Hypertension: Classification and Pathogenesis – Concept | Pharmacology | JoVe

  https://app.jove.com/science-education/15361/pulmonary-hypertension-classification-and-pathogenesis

  Pulmonary hypertension, or PH, denotes the resting mean pulmonary arterial pressure of 25 mm Hg or higher. […] PAH is a rare, fatal condition characterized by vascular changes in small arteries and arterioles, leading to elevated pulmonary arterial pressure and vascular resistance. […] The key mechanisms in PAH include pulmonary vascular remodeling, sustained pulmonary vasoconstriction, in situ thrombosis, and stiffening of the pulmonary vascular wall. […] Decreased vasoactive mediators like prostacyclin and increased vasoconstrictors like ET-1 contribute to vasoconstriction. […] PAH, in particular, is a rare but fatal form of PH. It results in vascular changes in small arteries and arterioles, increasing pulmonary arterial pressure and vascular resistance. The key mechanisms involved in PAH include structural changes in the lung blood vessel, narrowing of the blood vessels or pulmonary vasoconstriction, in situ thrombosis (clotting within the blood vessels), and stiffening of the pulmonary vascular wall.

• #12 Pulmonary hypertension – Wikipedia

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

  The pathogenesis of pulmonary arterial hypertension (WHO Group I) involves the narrowing of blood vessels connected to and within the lungs. This makes it harder for the heart to pump blood through the lungs, as it is much harder to make water flow through a narrow pipe as opposed to a wide one. Over time, the affected blood vessels become stiffer and thicker, in a process known as fibrosis. The mechanisms involved in this narrowing process include vasoconstriction, thrombosis, and vascular remodeling (excessive cellular proliferation, fibrosis, and reduced apoptosis/programmed cell death in the vessel walls, caused by inflammation, disordered metabolism and dysregulation of certain growth factors). This further increases the blood pressure within the lungs and impairs their blood flow. In common with other types of pulmonary hypertension, these changes result in an increased workload for the right side of the heart.

• #13 Pathophysiology and new advances in pulmonary hypertension | BMJ Medicine

  https://bmjmedicine.bmj.com/content/2/1/e000137

  Major technological advances in genetic and epigenomic sequencing have rapidly increased our understanding of the contributions of these processes to the predisposition, pathobiology, and severity of pulmonary arterial hypertension. […] The prevalence of pulmonary arterial hypertension is higher in female individuals, with a female to male ratio in all forms of pulmonary arterial hypertension of 1.4-4.1 to 1. […] The first phase of right ventricular adaptation to pulmonary arterial hypertension or pulmonary hypertension is characterised by compensatory right ventricular hypertrophy and an increase in contractility of 4-5-fold in response to its increased load. […] Right ventricular function predicts survival in patients with all forms of pulmonary hypertension.

• #14 Idiopathic Pulmonary Arterial Hypertension: Practice Essentials, Background, Pathophysiology

  https://emedicine.medscape.com/article/301450-overview

  The pathophysiology of IPAH is poorly understood. An insult (eg, hormonal, mechanical, other) to the endothelium may occur, possibly in the setting of increased susceptibility to pulmonary vascular injury (ie, multiple hit theory), resulting in a cascade of events characterized by vascular scarring, endothelial dysfunction, and intimal and medial (smooth muscle) proliferation. […] At least 15-20% of patients previously thought to have IPAH actually have a familial form of PAH involving at least one genetic defect. The most common genetic defect in these cases involves the BMPR-II gene. However, only about a third of affected patients with a family history of PAH have an identifiable BMPR-II mutation. This suggests that additional genetic abnormalities and/or additional external factors may exist that predispose individuals to developing PAH.

• #15 High-altitude Pulmonary Hypertension: an Update on Disease Pathogenesis and Management

  https://opencardiovascularmedicinejournal.com/VOLUME/10/PAGE/19/

  Scientific data suggest that genetics plays a role in the susceptibility to HAPH. For example, the Sherpa ethnic group living in Nepal has a Glu 298Asp polymorphism of the G allele of the NO synthase gene. The role of angiotensin converting enzyme (ACE) polymorphisms has also been studied. […] It is important to bear in mind that other factors may contribute to the development of elevated PH in people living at high altitude. For example, premenopausal women have a lower burden of HAPH compared to men. This observation may be explained by the stimulatory effects of female sex hormones on ventilatory drive. Indeed, the native Tibetan population has augmented ventilation, which is believed to be protective against the development of HAPH. […] In summary, hypoxic stimuli lead to an increase in pulmonary arterial vasoconstriction and vascular remodeling through the alteration of ion channel activity. Vascular remodeling includes the proliferation of smooth muscle cells in pulmonary vessels that are normally devoid of them and decreased apoptosis of these cells. Moreover, it also modulates the biochemical activity of pulmonary endothelium with a shift towards the production of substances such as endothelin-1. The role of genetic predisposition seems to be essential for the development of disease, but is not entirely understood at this time. Other factors and comorbidities may also play some role in selected circumstances.

• #16 Pulmonary hypertension: recognition, diagnosis and management – The Pharmaceutical Journal

  https://pharmaceutical-journal.com/article/ld/pulmonary-hypertension-recognition-diagnosis-and-management

  The pathophysiology of PH can vary depending on the underlying aetiology. This section will focus primarily on Group I PH, known as pulmonary arterial hypertension (PAH). PAH is further categorised according to its aetiology, with idiopathic PAH comprising the majority of cases, followed by PAH associated with connective tissue diseases and congenital heart disorders. It is commonly characterised by angioproliferative vasculopathy in the pulmonary arterioles. This affects pre-capillary arterioles by smooth muscle proliferation, dysfunction, inflammation and thrombosis, ultimately reducing lumen diameter, giving a disordered appearance. This in turn increases right ventricle afterload, with the resulting right heart failure being the most common cause of death. […] The pathogenesis of PAH is most likely multi-factorial, involving multiple pathways rather than a single mechanism. In all cases there is an imbalance of vasoconstricting and vasodilating substances in the pulmonary arteries. Increases in vasoconstricting substances (such as thromboxane, endothelin and serotonin) and reduced levels of vasodilatory substances (such as nitric oxide) are commonly observed in PAH patients. Vascular proliferation has also been implicated in PAH patients. Inappropriate activation of transcription factors can promote smooth muscle propagation.

• #17 Pulmonary Arterial Hypertension: Updates in Epidemiology and Evaluation of Patients

  https://www.ajmc.com/view/pulmonary-arterial-hypertension-updates-in-epidemiology-and-evaluation-of-patients

  Additionally, an imbalance exists between vasodilation and vasoconstriction favoring vasoconstriction with an increase in circulating vasoconstrictors (ie, thromboxane, endothelin, and serotonin) and a decrease in circulating vasodilators (ie, prostacyclin, nitric oxide [NO], and vasoactive intestinal polypeptide). […] The improved understanding of the pathophysiology of PAH has led to development of therapies targeting the NO pathway, prostacyclin pathway, and endothelin pathway. […] The pathology of PAH had previously been thought to be limited to the small pulmonary arteries; however, recent evidence suggests that systemic vascular manifestations also occur. […] Tragically, as the disease progresses, the compensatory mechanisms of the right heart can fail, and lead to premature death.

• #18 Pulmonary arterial hypertension – Wikipedia

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

  Pathogenic and inappropriate platelet activation coupled with endothelial injury leads to formation of micro-thrombi. […] PAH also involves the characteristic plexiform lesions which are growths in the walls of the arterioles consisting of dilated blood vessels which communicate with the bronchial artery and vaso vasorum. […] Various enzymes or transporters involved in vasodilation are differentially expressed in those with pulmonary arterial hypertension. […] PAH is associated with reduced prostacyclin synthase activity in the vascular smooth muscle cells, resulting in decreased prostacyclin (PGI2) levels (prostacyclin acts as a vasodilator and inhibitor of vascular smooth muscle proliferation). […] The vasoconstrictor and cell proliferation activator endothelin-1 is also more active in those with PAH. […] And those with PAH also have evidence of reduced Nitric oxide synthetase activity, resulting in lower levels of the vasodilator nitric oxide.

• #19 Pulmonary Hypertension: Classification and Pathogenesis – Concept | Pharmacology | JoVe

  https://app.jove.com/science-education/15361/pulmonary-hypertension-classification-and-pathogenesis

  Various bodily substances known as vasoactive mediators play a role in these processes. For example, nitric oxide (NO) and prostacyclin help to promote pulmonary vasodilation (widening of the blood vessels), which can alleviate PH. On the other hand, vasoconstrictors like endothelin-1 (ET-1) contribute to vasoconstriction and the proliferation of smooth muscle cells, potentially worsening PH.

• #20 Pulmonary Hypertension | IntechOpen

  https://www.intechopen.com/chapters/84915

  Regardless of the primary conditions, patients show similar pathophysiological pathways, such as augmented pulmonary arterioles contractility, endothelial dysfunction, proliferation of smooth muscle cells, and the presence of in situ thrombi. […] The transition from alveolar-capillary stress failure to remodeling is clinically reflected by the rise of PVR in patients with long-standing post-capillary PH who develop combined pre- and post-capillary PH. […] The three main modified pathways in PAH (NO, ET1, and PGI2) have been uncovered and targeted with appropriate pharmacological therapy, leading to an improvement in symptoms, quality of life, and survival of these patients.

• #21 Pulmonary Arterial Hypertension: Updates in Epidemiology and Evaluation of Patients

  https://www.ajmc.com/view/pulmonary-arterial-hypertension-updates-in-epidemiology-and-evaluation-of-patients

  Autoantibodies, proinflammatory cytokines, and inflammatory infiltrates have also been implicated in the pathogenesis of PAH. […] Individuals with PAH have increased von Willebrand factor levels, plasma fibrinopeptide A, plasminogen activator inhibitor-1, serotonin (5-HT), and thromboxane. […] In addition, tissue plasminogen activator, thrombomodulin, NO, and PGI2 are decreased, creating an imbalance that favors thrombosis.

• #22 Pulmonary arterial hypertension – Wikipedia

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

  Pulmonary arterial hypertension (PAH) is characterized by increased pressure in the pulmonary arteries and arterioles (the pulmonary circulation proximal to the capillary bed). […] This pre-capillary pulmonary artery pressure being elevated is essential, and by definition a mean pulmonary artery pressure greater than 20 mmHg as measured by a right heart catheterization is required for the diagnosis. […] This pre-capillary pulmonary hypertension is confirmed with measuring pulmonary vascular resistance being greater than 3 Woods Units. […] Multiple pathophysiological changes have been observed in PAH. This includes an imbalance in apoptosis (programmed cell death) and proliferation of endothelial cells, resulting in intimal thickening as well as proliferation and hyperplasia of the smooth muscle cells constituting the muscular layer of the pulmonary arteries.

• #23 Pulmonary hypertension – Wikipedia

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

  In PVOD (WHO Group I’), pulmonary blood vessel narrowing occurs preferentially (though not exclusively) in post-capillary venous blood vessels. PVOD shares several characteristics with PAH, but there are also some important differences, for example differences in prognosis and response to medical therapy. […] Pathogenesis in pulmonary hypertension due to left heart disease (WHO Group II) is completely different in that constriction or damage to the pulmonary blood vessels is not the issue. Instead, the left heart fails to pump blood efficiently, leading to pooling of blood in the lungs and back pressure within the pulmonary system. This causes pulmonary edema and pleural effusions. […] In pulmonary hypertension due to lung diseases and/or hypoxia (WHO Group III), low levels of oxygen in the alveoli (due to respiratory disease or living at high altitude) cause constriction of the pulmonary arteries. This phenomenon is called hypoxic pulmonary vasoconstriction and it is initially a protective response to stop too much blood flowing to areas of the lung that are damaged and do not contain oxygen. When the alveolar hypoxia is widespread and prolonged, this hypoxia-mediated vasoconstriction occurs across a large portion of the pulmonary vascular bed and leads to an increase in pulmonary arterial pressure, with thickening of the pulmonary vessel walls contributing to the development of sustained pulmonary hypertension.

• #24

  https://www.archivesofmedicalscience.com/Pulmonary-hypertension-in-left-heart-disease,65206,0,2.html

  The increased pulmonary venous pressure results in disruption of alveolar-capillary walls termed alveolar-capillary stress failure, resulting in capillary leakage and acute alveolar edema. This acute stage is reversible. However with chronically increased pulmonary venous pressure there is irreversible remodeling of the alveolar-capillary membrane as a compensatory mechanism to decrease the frequency and severity of potentially life-threatening pulmonary edema. The remodeling affects both pulmonary venous and arterial system with thickening of the capillary endothelial and alveolar epithelial cell basement membranes and pulmonary veins. These changes reduce the permeability of the alveolar-capillary membrane to fluids, and prevent development of pulmonary edema. The process also results in muscularization of the arterioles and neointima formation along with medial hypertrophy of distal small pulmonary arteries leading to increased pulmonary vascular resistance.

• #25 Canine pulmonary hypertension, Part 1: An in-depth review of its pathophysiology and classifications

  https://www.dvm360.com/view/canine-pulmonary-hypertension-part-1-depth-review-its-pathophysiology-and-classifications

  Alveolar hypoxia also induces growth factors, such as platelet-derived growth factors A and B, vascular endothelial growth factor, endothelin, and serotonin. […] Pulmonary arterial vasoconstriction occurs in response to the stimulation of alpha-adrenergic receptors. […] Prostaglandins are hormone-like substances that are actively synthesized, metabolized, and released by the lungs. […] Thromboxane is associated with vasoconstriction and platelet activation. […] Nitric oxide stimulates the enzyme guanylate cyclase, which catalyzes guanosine triphosphate conversion to cyclic guanosine monophosphate (cGMP), leading to an increase in cGMP concentrations. […] Endothelin-1 causes vasoconstriction, stimulates growth factors and smooth muscle cell proliferation, and promotes vascular remodeling. […] Angiotensin II causes vasoconstriction and vascular remodeling. […] Canine pulmonary hypertension is a complex condition caused by an imbalance in pulmonary arterial vasoconstriction and vasodilation and is associated with enhanced platelet actions and vascular remodeling.

• #26 Pulmonary hypertension – Wikipedia

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

  In chronic thromboembolic pulmonary hypertension, or CTEPH (WHO Group IV), the initiating event is thought to be blockage or narrowing of the pulmonary blood vessels with unresolved blood clots; these clots can lead to increased pressure and shear stress in the rest of the pulmonary circulation, precipitating structural changes in the vessel walls (remodeling) similar to those observed in other types of severe pulmonary hypertension. This combination of vessel occlusion and vascular remodeling once again increases the resistance to blood flow and so the pressure within the system rises.

• #27 Pulmonary Hypertension: Diagnosis and Treatment | AAFP

  https://www.aafp.org/pubs/afp/issues/2016/0915/p463.html

  Pulmonary hypertension due to left heart disease is primarily a pulmonary venous process and likely results from passive pulmonary venous congestion with vasoconstriction and venous remodeling. […] In pulmonary hypertension due to lung disease and/or hypoxia, increases in pulmonary arterial pressures may arise from destruction of the alveolar capillary bed or chronic hypoxic vasoconstriction. […] Chronic thromboembolic pulmonary hypertension develops following thrombotic macrovascular obstruction with subsequent vasoconstriction and remodeling of the pulmonary arterial bed. […] Regardless of the mechanism, persistently increased pulmonary arterial pressure strains the thin-walled right ventricle. […] Ultimately, right ventricular failure is the most common cause of death in patients with pulmonary hypertension.

• #28 Pulmonary hypertension – Wikipedia

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

  The right ventricle is normally part of a low pressure system, with systolic ventricular pressures that are lower than those that the left ventricle normally encounters. As such, the right ventricle cannot cope as well with higher pressures, and although right ventricular adaptations (hypertrophy and increased contractility of the heart muscle) initially help to preserve stroke volume, ultimately these compensatory mechanisms are insufficient; the right ventricular muscle cannot get enough oxygen to meet its needs and right heart failure follows. […] As the blood flowing through the lungs decreases, the left side of the heart receives less blood. This blood may also carry less oxygen than normal. Therefore, it becomes harder and harder for the left side of the heart to supply sufficient oxygen to the rest of the body, especially during physical activity.

• #29 Novel insights and new therapeutic potentials for macrophages in pulmonary hypertension | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-024-02772-8

  Inflammation and immune processes underlie pulmonary hypertension progression. Two main different activated phenotypes of macrophages, classically activated M1 macrophages and alternatively activated M2 macrophages, are both involved in inflammatory processes related to pulmonary hypertension. […] Identifying the critical role of macrophages in pulmonary hypertension will contribute to a comprehensive understanding of this pathophysiological abnormality, and may provide new perspectives for pulmonary hypertension management. […] The infiltration of macrophages occurs mainly in perivascular areas and is involved in the pathogenesis of PH by coordinating the initiation and resolution of pulmonary inflammation. […] Both external and internal stimuli, such as genetic mutations, hypoxia, cold exposure, air pollution, and respiratory infection, can initiate immune responses and therefore lead to the proliferation of vascular cells, autoantibody formation, and dysregulated immunity.

• #30

  https://link.springer.com/article/10.1007/s10741-015-9519-2

  Novel experimental approaches based on application of next generation sequencing, bioinformatics and epigenetics research are also discussed as these are now being actively used to facilitate the discovery of novel gene mutations and mechanisms that regulate gene expression in PAH. […] Finally, we touch on recent discoveries concerning the role of inflammation and immunity in PAH pathobiology and how they are being targeted with immunomodulatory agents. […] We conclude that the field of PAH research is actively expanding and the major challenge in the coming years is to develop a unified theory that incorporates genetic and mechanistic data to address viable areas for disease modifying drugs that can target key processes that regulate the evolution of vascular pathology of PAH.

• #31 Roles of LncRNAs in the Pathogenesis of Pulmonary Hypertension

  https://www.imrpress.com/journal/RCM/25/6/10.31083/j.rcm2506217

  Pulmonary hypertension (PH) is a persistently progressive, incurable, multifactorial associated fatal pulmonary vascular disease characterized by pulmonary vascular remodeling. […] Long noncoding RNAs (lncRNAs) are involved in regulating pathological processes such as pulmonary vasoconstriction, thickening, remodeling, and inflammatory cell infiltration in PH by acting on different cell types. […] Because of their differential expression in PH patients, as demonstrated by the observation that some lncRNAs are significantly upregulated while others are significantly downregulated in PH patients, lncRNAs are potentially useful biomarkers for assessing disease progression and diagnosis or prognosis in PH patients. […] This article provides an overview of the different mechanisms by which lncRNAs are involved in the pathogenesis of PH.

• #32 Pathophysiology and Treatment of Pulmonary Arterial Hypertension

  https://www.mdpi.com/1422-0067/25/2/1166

  This Special Issue primarily concentrates on PAH, classified as Group 1, with the objective of elucidating recently identified cellular pathogenesis mechanisms. […] Ryanto et al. reviewed the role of activin/inhibin signaling as a crucial mediator in the development of PAH and its potential as a therapeutic target to enhance patient outcomes. […] Pullamsetti et al. discussed the significance of the PDGFR-CSF1R-c-KIT signaling network in PAH pathogenesis and proposed that inhibiting all three nodes could be a novel therapeutic strategy. […] Despite advancements of pulmonary vasodilators over the past two decades, PAH and CTEPH remain serious conditions with significant morbidity and mortality. […] To date, no treatments directly addressing the underlying causes of pulmonary arteriopathy have been developed.

• #33 Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension | bioRxiv

  https://www.biorxiv.org/content/10.1101/2024.02.11.579846v1

  Endothelial fatty acid-binding proteins contribute to the pathogenesis of pulmonary hypertension. […] Pulmonary arterial hypertension (PAH) is a devastating disease characterized by obliterative vascular remodeling and persistent increase of vascular resistance, leading to right heart failure and premature death. Understanding the cellular and molecular mechanisms will help develop novel therapeutic approaches for PAH patients. Recent studies showed that FABP4 and FABP5 were expressed in ECs across multiple tissues and circulating FABP4 level was elevated in the PAH patients. However, the role of endothelial FABP4/5 in the pathogenesis of PAH remains undetermined. […] Both FABP4 and FABP5 were highly induced in ECs of CKO mice and PAECs from IPAH patients, and in whole lungs of PH rats. Plasma levels of FABP4/5 were upregulated in IPAH patients and directly correlated with severity of hemodynamics and biochemical parameters. Genetic deletion of both Fabp4 and 5 in CKO mice caused a reduction of right ventricular systolic pressure (RVSP) and RV hypertrophy, attenuated pulmonary vascular remodeling and prevented the right heart failure. Fabp4/5 deletion also normalized EC glycolysis, reduced ROS and HIF-2α expression, and decreased aberrant EC proliferation in CKO lungs. […] PH causes aberrant expression of FABP4/5 in pulmonary ECs which leads to enhanced ECs glycolysis and hyperproliferation, contributing to the accumulation of arterial ECs and vascular remodeling and exacerbating the disease.

• #34 An embryonic artery-forming niche reactivates in pulmonary arterial hypertension | bioRxiv

  https://www.biorxiv.org/content/10.1101/2025.05.02.651303v1

  Developmental mechanisms that precisely orchestrate cell fate and tissue architecture in organogenesis can be aberrantly reactivated to cause disease. Here we identify a previously uncharacterized population of endothelial niche cells, defined by the pioneer factor early B cell factor 1 (EBF1), that promotes both the development and pathological remodeling of pulmonary arteries (PAs). […] In adult PAH, the embryonic artery-forming niche is reactivated. The normally quiescent Aplnr+ general capillary stem cells re-enter the cell cycle and regenerate arterial ECs and Ebf1+ ECs. By expressing key vasculotrophic signals including Apelin, Cxcl12/Cxcr4, Notch, and Tgf-β, these Ebf1+ ECs promote angiogenesis, neo-arterialization, and neo-muscularization in a maladaptive process echoing their role in development. Our findings define a novel developmental mechanism featuring unusually transient PA organizing cells. We suggest their reemergence in adulthood drives vascular pathology and that targeting these Ebf1+ ECs could halt or reverse PAH.

• #35 Azthena logo with the word Azthena

  https://www.news-medical.net/news/20250506/Hidden-heart-and-lung-damage-detected-in-patients-with-long-COVID.aspx

  Patients suffering from long COVID may exhibit persistent inflammation in the heart and lungs for up to a year following SARS-CoV-2 infection-even when standard medical tests return normal results-potentially placing them at elevated risk for future cardiac and pulmonary conditions. […] These abnormalities could serve as early warning signs of diseases such as heart failure, valvular heart disease, and pulmonary hypertension. […] We believe long COVID results in an inflammatory response that may predispose patients to premature coronary artery disease, pulmonary hypertension, and valvular damage such as stenosis or regurgitation. […] This study highlights the unique power of hybrid PET/MRI imaging to uncover hidden disease processes in long COVID patients. […] We now have objective evidence that can guide earlier detection and potentially prevent future cardiopulmonary events.

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