Pulmonary Vascular Remodeling Correlates with Lung Eggs and Cytokines in Murine Schistosomiasis

Crosby, Alexi; Jones, Frances M.; Southwood, Mark; Stewart, Susan; Schermuly, Ralph Theo; Butrous, Ghazwan; Dunne, David W.; Morrell, Nicholas W.

doi:10.1164/rccm.200903-0355oc

Cited by 104 publications

(143 citation statements)

References 29 publications

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“…For induction of PAH due to CH, groups of male mice (8-12 wk) were maintained in a normobaric hypoxic chamber (FiO 2 10%) for up to 21 d. Mice were weighed then anesthetized (isoflurane) and right-sided heart catheterization was performed through the right jugular using a pressure-volume loop catheter (Millar) (40)(41)(42). Blood was taken for hemodynamic assessment.…”

Section: Methodsmentioning

confidence: 99%

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Cowburn

Crosby

Macías

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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146

151

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Hypoxic pulmonary vasoconstriction is correlated with pulmonary vascular remodeling. The hypoxia-inducible transcription factors (HIFs) HIF-1α and HIF-2α are known to contribute to the process of hypoxic pulmonary vascular remodeling; however, the specific role of pulmonary endothelial HIF expression in this process, and in the physiological process of vasoconstriction in response to hypoxia, remains unclear. Here we show that pulmonary endothelial HIF-2α is a critical regulator of hypoxia-induced pulmonary arterial hypertension. The rise in right ventricular systolic pressure (RVSP) normally observed following chronic hypoxic exposure was absent in mice with pulmonary endothelial HIF-2α deletion. The RVSP of mice lacking HIF-2α in pulmonary endothelium after exposure to hypoxia was not significantly different from normoxic WT mice and much lower than the RVSP values seen in WT littermate controls and mice with pulmonary endothelial deletion of HIF-1α exposed to hypoxia. Endothelial HIF-2α deletion also protected mice from hypoxia remodeling. Pulmonary endothelial deletion of arginase-1, a downstream target of HIF-2α, likewise attenuated many of the pathophysiological symptoms associated with hypoxic pulmonary hypertension. We propose a mechanism whereby chronic hypoxia enhances HIF-2α stability, which causes increased arginase expression and dysregulates normal vascular NO homeostasis. These data offer new insight into the role of pulmonary endothelial HIF-2α in regulating the pulmonary vascular response to hypoxia.A lveolar hypoxia affects vascular flow in the pulmonary vascular bed via an immediate vasoconstrictor response (hypoxic pulmonary vasoconstriction, or HPV) (1). This reduces perfusion of regions of the lung with lowered levels of airflow (2). In conditions including chronic obstructive pulmonary disease (3), idiopathic pulmonary fibrosis (4), and at high altitude (5), HPV probably contributes to persistent increases in pulmonary arterial pressures. This in turn is correlated with reduced plasticity of the vascular bed, sustained pulmonary vascular remodeling, and, ultimately, debilitating right ventricular hypertrophy (RVH) and failure (2).The hypoxia-inducible factors (HIFs) are transcription factors and key regulators of the molecular response to hypoxia. The targets of HIFs include genes controlling vascularization, cellular proliferation, migration, and metabolism (6-11). A wellcharacterized animal model of hypoxia-induced pulmonary hypertension involves exposure to chronic hypoxia (CH), typically 10-12% inspired oxygen. This results in extensive vascular remodeling, marked pulmonary hypertension and RVH over a period of a few weeks. Exposure to CH in rodents results in vasoconstriction and a pattern of vascular remodeling that is reminiscent of humans with hypoxia-associated pulmonary hypertension (12, 13).Mice that are hemizygous for either of the HIF isoforms, HIF-1α (14) or HIF-2α (15), have been shown to have attenuated pulmonary vascular remodeling following experimental CH. Conditional de...

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Section: Methodsmentioning

confidence: 99%

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Cowburn

Crosby

Macías

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

146

151

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“…1). Only a few murine or rodent models recapitulate this pathological feature, eg, mice exposed to ovalbumin or aspergillus 2 or to schistosomiasis, 3 rats treated with the vascular endothelial receptor blocker Sugen 5416, exposed to chronic hypoxia and recovered in room air, 4 mice that overexpress IL-6 and are subjected to chronic hypoxia, 5 or mice that overexpress S100A4. 6 The latter mice, when over 1 year of age, can on rare occasions "spontaneously" develop severe neointimal lesions.…”

mentioning

confidence: 99%

Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

Kim

Haghighat

Spiekerkoetter

et al. 2011

The American Journal of Pathology

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Previously, we reported that murine gammaherpesvirus-68 (M1-MHV-68) induces pulmonary artery (PA) neointimal lesions in S100A4-overexpressing, but not in wild-type (C57), mice. Lesions were associated with heightened lung elastase activity and PA elastin degradation. We now investigate a direct relationship between elastase and PA neointimal lesions, the nature and source of the enzyme, and its presence in clinical disease. We found an association exists between the percentage of PAs with neointimal lesions and elastin fragmentation in S100A4 mice 6 months after viral infection. Confocal microscopy documented the heightened susceptibility of S100A4 versus C57 PA elastin to degradation by elastase. A transient increase in lung elastase activity occurs in S100A4 mice, 7 days after M1-MHV-68, unrelated to inflammation or viral load and before neointimal lesions. Administration of recombinant elafin, an elastasespecific inhibitor, ameliorates early increases in serine elastase and attenuates later development of neointimal lesions. Neutrophils are the source of elevated elastase (NE) in the S100A4 lung, and NE mRNA and protein levels are greater in PA smooth muscle cells (SMC) from S100A4 mice than from C57 mice. Furthermore, elevated NE is observed in cultured PA SMC from idiopathic PA hypertension versus that in control lungs and localizes to neointimal lesions. Thus, PA SMC produce NE, and heightened production and activity of NE is linked to experimental and clinical pulmonary vascular disease. (Am J Pathol

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“…mansoni modulates its host's immune system to survive. In the course of schistosomiasis, worms, eggs and their soluble antigens, i.e., a complex mixture of proteins, glycoproteins and glycolipids, interact with vascular endothelium [49] and myocytes causing morphological alterations [4,8,34,35,[50][51][52]. Previous data showed that schistosomiasis is associated with a reduction of mesenteric endothelial eNOS expression and ATP-induced NO production [15].…”

Section: Discussionmentioning

confidence: 99%

Endothelial P2X7 receptors’ expression is reduced by schistosomiasis

Oliveira

Coutinho‐Silva

Silva

2012

Purinergic Signalling

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Endothelial cells control vascular tone, permeability and leukocyte transmigration and are modulated by pro-inflammatory mediators. Schistosomiasis is an intravascular disease associated with inflammation, therefore altering endothelial cells' phenotype. Purinergic P2X7 receptors (P2X7R) play an important role in inflammation; however, the impact of the disease upon endothelial P2X7R function or expression has not been explored. Using ethidium bromide uptake to investigate P2X7R function, we observed that the effects of ATP (3 mM) and the P2X7R agonist 3′-O-(4-benzoyl)-ATP (BzATP) were smaller in mesenteric endothelial cells from the Schistosoma mansoni-infected group than in the control group. In the control group, BzATP induced endothelial nitric oxide production, which was blocked by the P2X7R antagonists KN-62 and A740003. However, in the infected group, we observed a reduced effect of BzATP and no effect of both P2X7R antagonists, suggesting a downregulation of endothelial P2X7R in schistosomiasis. We observed similar results in both infected and P2X7R −/− groups, which were also comparable to data obtained with KN-62-or A740004-treated control cells. Data from Western blot and immunocytochemistry assays confirmed the reduced expression of P2X7R in the infected group. In conclusion, our data show a downregulation of P2X7R in schistosomiasis infection, which likely limits the infection-related endothelial damage.

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Pulmonary Vascular Remodeling Correlates with Lung Eggs and Cytokines in Murine Schistosomiasis

Abstract: This study provides evidence for extensive pulmonary vascular remodeling, despite the absence of RV hypertrophy, in a mouse model of schistosomiasis, including the formation of plexiform-like lesions. Inflammatory cytokines and lung egg burden may contribute to vascular lesion formation.

Cited by 104 publications

References 29 publications

HIF2α–arginase axis is essential for the development of pulmonary hypertension

HIF2α–arginase axis is essential for the development of pulmonary hypertension

Neutrophil Elastase Is Produced by Pulmonary Artery Smooth Muscle Cells and Is Linked to Neointimal Lesions

Endothelial P2X7 receptors’ expression is reduced by schistosomiasis

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