The vascular perspective on acute and chronic lung disease

Borek, Izabela; Birnhuber, Anna; Voelkel, Norbert F.; Marsh, Leigh M.; Kwapiszewska, Grazyna

doi:10.1172/jci170502

Cited by 15 publications

(19 citation statements)

References 191 publications

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“…Patients were not matched based on underlying CLD for several reasons. Several pathophysiological mechanisms implicated in the development of CLD-PH are shared across lung diseases, including the impact of exposure to chronic hypoxia and cigarette smoke and the influences of oxidative stress and cellular senescence on the pulmonary vasculature [ 16 , 17 ]. Therefore, the “vascular phenotype” of CLD may reflect a common pathway of divergent upstream diagnoses, more likely to be captured and characterised with our inclusive approach.…”

Section: Methodsmentioning

confidence: 99%

“…Importantly, the pathophysiology and clinical profile of Group 3 PH share features across CLDs, but are simultaneously heterogenous. For example, shared mechanisms of pulmonary vascular injury are implicated in both COPD-PH and interstitial lung disease-PH with common aspects of clinical presentation [ 16 , 17 ]. However, divergent disease mechanisms exist and, when present, Group 3 PH occurs across a wide haemodynamic spectrum that strongly influences mortality risk [ 2 , 3 ].…”

Section: Introductionmentioning

confidence: 99%

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Cluster analysis identifies novel real-world lung disease-pulmonary hypertension sub-phenotypes: implications for treatment response

Johnson,

Wang,

Winter

et al. 2024

ERJ Open Res

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BackgroundClinical trials repurposing pulmonary arterial hypertension (PAH) therapies to patients with lung disease- or hypoxia-pulmonary hypertension (Group 3 PH) have failed to show a consistent benefit. However, Group 3 PH clinical heterogeneity suggests robust phenotyping may inform detection of treatment-responsive subgroups. We hypothesized that cluster analysis would identify sub-phenotypes with differential responses to oral PAH therapy.MethodsTwo k-means analyses were performed on a national cohort of U.S. Veterans with Group 3 PH; an inclusive model (I) of all treated patients (n=196) and a hemodynamic model (H) limited to patients with right heart catheterisations (RHC) (n=112). The primary outcome was organ failure or all-cause mortality by cluster. An exploratory analysis evaluated within-cluster treatment effects.ResultsThree distinct clusters of Group 3 PH patients were identified. In the “inclusive model” (C1I=43, 21.9%; C2I=102, 52.0%; C3I=51, 26.0%) lung disease and spirometry drove cluster assignment whereas RHC data surpassed the importance of these variables in the hemodynamic model (C1H=44, 39.3%; C2H=43, 38.4%; C3H=25, 22.3%). In the hemodynamic model, compared to C3H, C1Hexperienced the greatest hazard for respiratory failure or death (HR 6.1 [95% CI 3.2, 11.8]). In an exploratory analysis, cluster determined treatment response (p=0.006). Conclusions regarding within-cluster treatment responses were limited by significant differences between select variables in the treated and untreated groups.ConclusionsCluster analysis identifies novel real-world sub-phenotypes of Group 3 PH patients with distinct clinical trajectories. Future studies may consider this methodologic approach to identify subgroups of heterogeneous patients that may be responsive to existing pulmonary vasodilatory therapies.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension sub-phenotypes: implications for treatment response

Johnson,

Wang,

Winter

et al. 2024

ERJ Open Res

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“…This is a particularly serious condition because the resultant impairment of gas exchange leads to systemic hypoxaemia. (Collins, Blank et al 2013, Matthay, Zemans et al 2019, Borek, Birnhuber et al 2023). However, the role of reduced shear stress in oedema formation in the lungs following IRI and whether increasing shear stress towards normal values can contribute to restoration of endothelial barrier function in this condition has not previously been examined.…”

Section: Introductionmentioning

confidence: 99%

Shear stress-induced restoration of pulmonary endothelial barrier function following ischaemia reperfusion injury requires VEGFR2 signalling

Walsh,

Kostyunina,

Boylan

et al. 2024

Preprint

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Normal physiological shear stress produced by blood flow is sensed by the vascular endothelium and required for the maintenance of both the normal structure and barrier function of the endothelium. Many common, critical illnesses are characterised by periods of abnormally reduced or absent shear stress e.g. haemorrhagic shock, myocardial infarction and pulmonary embolism and are complicated by oedema formation following restoration of normal perfusion (IRI).We tested the hypothesis that, in lungs injured by a period of ischaemia and reperfusion (IRI), reduced shear stress contributes to increased endothelial barrier permeability and oedema formation following the restoration of perfusion. Furthermore, we examined the role of VEGFR2 as a mechanosensor in the response of the pulmonary endothelium to altered shear stress in this condition.Following IRI, we perfused isolated ventilated mouse lungs with a low viscosity solution (LVS) or a higher, physiological viscosity solution (PVS) at constant flow to produce differing shear stresses on the endothelium of the intact pulmonary circulation. Lungs perfused with LVS developed pulmonary oedema due to increased endothelial permeability whereas those perfused with PVS were protected from oedema formation by reduced endothelial permeability. This effect of PVS required normal VEGFR2 tyrosine kinase activity but was unaffected by blocking VEGFA binding to the receptor.These data show for the first time that shear stress has an important role in restoring endothelial barrier function in the pulmonary circulation following injury and have important implications for the treatment of pulmonary oedema in critically ill patients following ischaemia reperfusion injury.

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“…The lung’s unique anatomical and physiological characteristics are critical to understanding the pathogenesis of ALI/ARDS. As the most highly vascularized organ, the lung’s extensive network of microvessels is essential for gas exchange and is particularly vulnerable to injury [ 2 , 7 , 8 , 9 , 10 ]. These microvessels are lined by endothelial cells (ECs), which account for about half of all lung cells [ 7 , 10 , 11 , 12 ].…”

Section: Introductionmentioning

confidence: 99%

“…As the most highly vascularized organ, the lung’s extensive network of microvessels is essential for gas exchange and is particularly vulnerable to injury [ 2 , 7 , 8 , 9 , 10 ]. These microvessels are lined by endothelial cells (ECs), which account for about half of all lung cells [ 7 , 10 , 11 , 12 ]. ECs are pivotal in maintaining vascular integrity and lung function, regulating processes such as blood vessel tone, blood fluidity, and the barrier function against pathogens and fluid leakage [ 7 , 13 , 14 , 15 , 16 ].…”

Section: Introductionmentioning

confidence: 99%

Roles of Macrophages and Endothelial Cells and Their Crosstalk in Acute Lung Injury

Osorio-Valencia,

Zhou

2024

Biomedicines

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Acute lung injury (ALI) and its severe form, acute respiratory distress syndrome (ARDS), present life-threatening conditions characterized by inflammation and endothelial injury, leading to increased vascular permeability and lung edema. Key players in the pathogenesis and resolution of ALI are macrophages (Mφs) and endothelial cells (ECs). The crosstalk between these two cell types has emerged as a significant focus for potential therapeutic interventions in ALI. This review provides a brief overview of the roles of Mφs and ECs and their interplay in ALI/ARDS. Moreover, it highlights the significance of investigating perivascular macrophages (PVMs) and immunomodulatory endothelial cells (IMECs) as crucial participants in the Mφ–EC crosstalk. This sheds light on the pathogenesis of ALI and paves the way for innovative treatment approaches.

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The vascular perspective on acute and chronic lung disease

Cited by 15 publications

References 191 publications

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension sub-phenotypes: implications for treatment response

Cluster analysis identifies novel real-world lung disease-pulmonary hypertension sub-phenotypes: implications for treatment response

Shear stress-induced restoration of pulmonary endothelial barrier function following ischaemia reperfusion injury requires VEGFR2 signalling

Roles of Macrophages and Endothelial Cells and Their Crosstalk in Acute Lung Injury

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