The Effects of Chronic Hypoxia on Inflammation and Pulmonary Vascular Function

Stenmark, Kurt R.; Pugliese, Steven C.; Poth, Jens M.; Frid, Maria G.; Gerasimovskaya, Evgenia; Nozik‐Grayck, Eva; Kasmi, Karim C. El

doi:10.1007/978-3-319-23594-3_5

Cited by 2 publications

(4 citation statements)

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“…The essential mechanisms are: increasing the heart and respiratory rates, a secondary polycythaemia, haemoconcentration derived from reduced plasma volume caused by respiratory evaporative water loss and polyuria and increased ventilatory response 37 43 44. When acute exposure lasts longer than 28 days, more efficient and prolonged mechanisms take place, including sustained polycythaemia, endothelium changes, reduced vascular resistance, nitric oxide-mediated hypotension and angiogenesis 45–48. Acute exposure to high-altitude hypoxia triggers a series of events that produce a hypercoagulable state 24.…”

Section: Discussionmentioning

confidence: 99%

Chronic high-altitude exposure and the epidemiology of ischaemic stroke: a systematic review

et al. 2022

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IntroductionAbout 5.7% of the world population resides above 1500 m. It has been hypothesised that acute exposure to high-altitude locations can increase stroke risk, while chronic hypoxia can reduce stroke-related mortality.ObjectiveThis review aims to provide an overview of the available evidence on the association between long-term high-altitude exposure and ischaemic stroke.DesignA systematic review was performed from 1 January 1960 to 1 December 2021 to assess the possible link between high-altitude exposure and ischaemic stroke. The AMED, EMBASE, Cochrane Library, PubMed, MEDLINE, the Europe PubMed Central and the Latin-American bibliographic database Scielo were accessed using the University of Southampton library tool Delphis. In this review, we included population and individual-based observational studies, including cross-sectional and longitudinal studies except for those merely descriptive individual-based case reports. Studies were limited to humans living or visiting high-altitude locations for at least 28 days as a cut-off point for chronic exposure.ResultsWe reviewed a total of 1890 abstracts retrieved during the first step of the literature review process. The authors acquired in full text as potentially relevant 204 studies. Only 17 documents met the inclusion criteria and were finally included. Ten studies clearly suggest that living at high altitudes may be associated with an increased risk of stroke; however, five studies suggest that altitude may act as a protective factor for the development of stroke, while two studies report ambiguous results.ConclusionsThis review suggests that the most robust studies are more likely to find that prolonged living at higher altitudes reduces the risk of developing stroke or dying from it. Increased irrigation due to angiogenesis and increased vascular perfusion might be the reason behind improved survival profiles among those living within this altitude range. In contrast, residing above 3500 m seems to be associated with an apparent increased risk of developing stroke, probably linked to the presence of polycythaemia and other associated factors such as increased blood viscosity.

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Section: Discussionmentioning

confidence: 99%

Chronic high-altitude exposure and the epidemiology of ischaemic stroke: a systematic review

et al. 2022

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“…Although the proinflammatory processes in PH are extensively investigated, the initiating mechanisms remain unclear. Pulmonary vascular fibroblasts have been recognized to initiate and facilitate recruitment of monocytes/macrophages to perivascular adventitia and their subsequent activation toward a pro-inflammatory state (2,9,13,34,39).…”

Section: Discussionmentioning

confidence: 99%

“…Pulmonary hypertension (PH) is a chronic and progressive cardiopulmonary disease associated with a sustained perivascular inflammation, severe vascular remodeling and right heart failure (1)(2)(3)(4)(5)(6). It is increasingly appreciated that inflammation, primarily characterized by early and persistent accumulation of perivascular macrophages, plays a critical role in vascular remodeling process associated with PH (2)(3)(4)(7)(8)(9)(10)(11). Recent studies have interrogated macrophage activation, relative to time and compartment (interstitial vs alveolar), using flow cytometric approaches in combination with RNA sequencing (RNAseq) in hypoxic mouse models of PH (11,12).…”

Section: Introductionmentioning

confidence: 99%

“…Hypoxia-induced changes in the interstitial macrophages (IMs) included mTORC1 signaling, metabolism, and activation of innate immune pathways, all well described with regard to hypoxia and PH (12). Although the role of innate immune pathways, including NF-kB, IL-1B and IL-6 are well described with regard to their roles in PH, very little is known regarding their roles in the context of macrophages in PH, especially with regard to mechanisms of activation (3,9).…”

Section: Introductionmentioning

confidence: 99%

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Complement-containing small extracellular vesicles from adventitial fibroblasts induce proinflammatory and metabolic reprogramming in macrophages

Kumar¹,

Frid²,

Zhang³

et al. 2021

JCI Insight

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Pulmonary hypertension (PH) is a severe cardiopulmonary disease characterized by complement-dependent, fibroblast-induced perivascular accumulation and proinflammatory activation of macrophages. We hypothesized that, in PH, nanoscale-sized small extracellular vesicles (sEVs), released by perivascular/adventitial fibroblasts, are critical mediators of complement-dependent pro-inflammatory activation of macrophages. Pulmonary adventitial fibroblasts were isolated from calves with severe PH (PH-Fibs) and age-matched controls (CO-Fibs). PH-Fibs exhibited increased secretion of sEVs, compared to CO-Fibs, and sEV biological activity was tested on mouse and bovine bone marrow-derived macrophages (BMDMs) and showed similar responses. PH-Fib-sEVs induced augmented expression of pro-inflammatory cytokines/chemokines and metabolic genes in BMDMs, compared to CO-Fib-sEVs.Pharmacological blockade of exosome release from PH-Fibs resulted in significant attenuation of pro-inflammatory activation of BMDMs. "Bottom-up" proteomic analyses revealed significant enrichment of complement and Coagulation cascades in PH-Fib-sEVs, including augmented expression of complement component C3. We therefore examined whether PH-Fib-sEVs-mediated pro-inflammatory activation of BMDMs was complement C3-dependent. Treatment of PH-Fibs with siC3-RNA significantly attenuated the capacity of PH-Fib-sEVs for pro-inflammatory activation of BMDMs. PH-Fib-sEVs mediated pro-glycolytic alterations and complement-dependent activation of macrophages toward a pro-inflammatory phenotype, as confirmed by metabolomic studies. Thus, fibroblast-released sEVs can serve as critical mediators of complementinduced perivascular/microenvironmental inflammation in PH.

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The Effects of Chronic Hypoxia on Inflammation and Pulmonary Vascular Function

Cited by 2 publications

References 244 publications

Chronic high-altitude exposure and the epidemiology of ischaemic stroke: a systematic review

Chronic high-altitude exposure and the epidemiology of ischaemic stroke: a systematic review

Complement-containing small extracellular vesicles from adventitial fibroblasts induce proinflammatory and metabolic reprogramming in macrophages

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