Pulmonary arterial remodeling induced by a Th2 immune response

Daley, E.; Emson, Claire; Guignabert, Christophe; Malefyt, René de Waal; Louten, Jennifer; Kurup, Viswanath P.; Hogaboam, Cory M.; Taraseviciene‐Stewart, Laimute; Voelkel, Norbert F.; Rabinovitch, Marlene; Grünig, Ekkehard; Grünig, Gabriele

doi:10.1083/jcb1803oia9

Cited by 66 publications

(125 citation statements)

References 27 publications

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“…Interestingly, formation of these neointimal lesions was not sufficient to elevate the right ventricular systolic pressure or to cause right ventricular hypertrophy (see Supplemental Figure S2 at http://ajp.amjpathol.org), a finding also observed in other models with neointimal lesions. 2 This may reflect the fact that the lesions are present in less than half of the intra-acinar PAs and are not occlusive, so the pulmonary blood flow could easily be diverted to vessels without these abnormalities. We found no quantitative evidence of differences in muscularization or loss of peripheral arteries following viral inoculation (data not shown).…”

Section: Fragmentation Of Pa Elastin In S100a4 Mice Is Associated Witmentioning

confidence: 99%

“…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.…”

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confidence: 99%

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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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Section: Fragmentation Of Pa Elastin In S100a4 Mice Is Associated Witmentioning

confidence: 99%

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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“…Several reports have indicated that HIMF and its related molecules play a key role in the alternative (Th2) activation of macrophages (27,28), and are involved in Th2-dependent, asthma-induced airway remodeling (29). HIMF is also up-regulated in the newly described Th2 model of pulmonary arterial remodeling (30). HIMF itself is activated by the Th2 pathway via IL-4 and IL-13 activation of a Stat6 site in its promoter region (31).…”

Section: Clinical Relevancementioning

confidence: 99%

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Angelini¹,

Su²,

Yamaji-Kegan³

et al. 2009

Am J Respir Cell Mol Biol

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Scleroderma is a systemic, mixed connective tissue disease that can impact the lungs through pulmonary fibrosis, vascular remodeling, and the development of pulmonary hypertension and right heart failure. Currently, little is known about the molecular mechanisms that drive this condition, but we have recently identified a novel gene product that is up-regulated in a murine model of hypoxia-induced pulmonary hypertension. This molecule, known as hypoxia-induced mitogenic factor (HIMF), is a member of the newly described resistin gene family. We have demonstrated that HIMF has mitogenic, angiogenic, vasoconstrictive, inflammatory, and chemokine-like properties, all of which are associated with vascular remodeling in the lung. Here, we demonstrate that the human homolog of HIMF, resistin-like molecule (RELM)-b, is expressed in the lung tissue of patients with scleroderma-associated pulmonary hypertension and is up-regulated compared with normal control subjects. Immunofluorescence colocalization revealed that RELM-b is expressed in the endothelium and vascular smooth muscle of remodeled vessels, as well as in plexiform lesions, macrophages, T cells, and myofibroblastlike cells. We also show that addition of recombinant RELM-b induces proliferation and activation of ERK1/2 in primary cultured human pulmonary endothelial and smooth muscle cells. These results suggest that RELM-b may be involved in the development of scleroderma-associated pulmonary hypertension.

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“…Waxman and colleagues have identified BCL6, a master transcriptional repressor affecting hundreds of genes, as a male-biased downstream effector of PY-STAT5 activation (27,(46)(47)(48). Our attention to BCL6 resulted from (a) the knowledge that this master regulator is involved in regulating B-cell development and function and follicular T helper cell function, and its genetic deletion results in a hypercytokine production state, which includes pulmonary vasculitis (118)(119)(120); (b) that STAT5a/b and BCL6 are expressed ubiquitously in different tissues and function, respectively, as master transcription activator and master transcription repressor (27); and (c) that several investigators have proposed that PH pathogenesis involves a component of localized pulmonary vascular inflammation (121)(122)(123). Thus, a reduction in BCL6 in cells in obliterative lesions of PH (Figure 7) would enhance localized proinflammatory cytokine production (plus changes in expression of hundreds of additional genes) (27,118,119).…”

Section: Stat5a/b and Bcl6 In Vascular Cellsmentioning

confidence: 99%

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

Sehgal

Yang

Miller

2015

Mol Med

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Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two-to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a wellcharacterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male ("pulsatile") versus female ("more continuous") temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations.

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Pulmonary arterial remodeling induced by a Th2 immune response

Cited by 66 publications

References 27 publications

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

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

Resistin-Like Molecule-β in Scleroderma-Associated Pulmonary Hypertension

Hypothesis: Neuroendocrine Mechanisms (Hypothalamus-Growth Hormone-STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

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