IL-13 receptor α<sub>2</sub>-arginase 2 pathway mediates IL-13-induced pulmonary hypertension

Cho, Won‐Kyung; Liu, Changmin; Kang, Min Jong; Huang, Yan; Giordano, Frank J.; Lee, Patricia; Trow, Terence K.; Homer, Robert J.; Sessa, William C.; Elias, Jack A.

doi:10.1152/ajplung.00101.2012

Cited by 46 publications

(49 citation statements)

References 49 publications

(59 reference statements)

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“…Munitz and colleagues (31) also found up-regulation of IL-13 in BAL during OVA-induced acute lung inflammation. A recent study with IL-13 transgenic mice showed that IL-13 overexpression can induce PH and vascular remodeling via arginase 2 and nitric oxide synthase 3 (33). Our current data do not support a role for IL-13 in inducing pulmonary vascular remodeling, and IL-13 is not likely vital to eosinophil recruitment.…”

Section: Discussioncontrasting

confidence: 93%

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Fan¹,

Meuchel²,

et al. 2015

Am J Respir Cell Mol Biol

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Resistin-like molecule a (RELMa) has mitogenic, angiogenic, vasoconstrictive, and chemokine-like properties and is highly relevant in lung pathology. Here, we used RELMa knockout (Retnla 2/2 ) mice to investigate the role of RELMa in pulmonary vascular remodeling after intermittent ovalbumin (OVA) challenge. We compared salineand OVA-exposed wild-type (WT) mice and found that OVA induced significant increases in right ventricular systolic pressure, cardiac hypertrophy, pulmonary vascular remodeling of intra-alveolar arteries, goblet cell hyperplasia in airway epithelium, and intensive lung inflammation, especially perivascular inflammation. Genetic ablation of Retnla prevented the OVA-induced increase in pulmonary pressure and cardiac hypertrophy seen in WT mice. Histological analysis showed that Retnla 2/2 mice exhibited less vessel muscularization, less perivascular inflammation, reduced medial thickness of intra-alveolar vessels, and fewer goblet cells in upper airway epithelium (250-600 mm) than did WT animals after OVA challenge. Gene expression profiles showed that genes associated with vascular remodeling, including those related to muscle protein, contractile fibers, and actin cytoskeleton, were expressed at a lower level in OVA-challenged Retnla 2/2 mice than in similarly treated WT mice. In addition, bronchoalveolar lavage from OVA-challenged Retnla 2/2 mice had lower levels of cytokines, such as IL-1b, -1 receptor antagonist, and -16, chemokine (C-X-C motif) ligand 1, -2, -9, -10, and -13, monocyte chemoattractant protein-1, macrophage colony-stimulating factor, TIMP metallopeptidase inhibitor-1, and triggering receptor expressed on myeloid cells-1, than did that from WT mice when analyzed by cytokine array dot blots. Retnla knockout inhibited the OVA-induced T helper 17 response but not the T helper 2 response. Altogether, our results suggest that RELMa is involved in immune response-induced pulmonary vascular remodeling and the associated increase in inflammation typically observed after OVA challenge.Keywords: resistin-like molecule a; pulmonary hypertension; vascular remodeling; inflammation; T helper 17 Clinical RelevanceWe have demonstrated that resistin-like a (RELMa) knockout mice inhibited pulmonary vascular remodeling and the increase in pulmonary pressure and cardiac hypertrophy in a model of allergen-induced pulmonary vascular remodeling. Further studies show that this prevention is associated with suppressed inflammation in the lung, involving a T helper 17 immune response. Our study reveals a novel function of RELMa on immune regulation in pulmonary hypertension and shows that it could be a novel therapeutic target for pulmonary hypertension.Resistin and resistin-like molecules (RELMs) have been identified as a family of cysteinerich small proteins that share no homology to any known hormone or cytokine (1-4). The RELM family has four murine isoforms (RELMa, RELMb, resistin, and RELMg) and two human isoforms (resistin and RELMb), all of which have a structurally conserved 10-c...

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Section: Discussioncontrasting

confidence: 93%

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Fan¹,

Meuchel²,

et al. 2015

Am J Respir Cell Mol Biol

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“…Other studies have shown that dysregulation of IL-13 signaling is present in human PAH, although whether IL-13 is pro-or antiproliferative remains unclear. 36,40,41 Consequent to these findings, we found evidence of enhanced PH in S. mansoniinfected mice lacking IL-13Rα2, suggesting that IL-13 signaling is an important mediator of the granulomatous and vascular response to schistosomiasis infection. 37 Thus, the IL-13 ligand and receptors may serve as novel biomarkers in PH and potential targets for receptor-directed therapeutic agents.…”

supporting

confidence: 71%

Schistosomiasis and the Pulmonary Vasculature (2013 Grover Conference Series)

Graham

Kumar

2014

Pulm. circ.

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Inflammation is associated with multiple forms of pulmonary arterial hypertension (PAH), including autoimmune (scleroderma) and infectious (HIV, schistosomiasis) etiologies. More than 200 million people worldwide are infected with Schistosoma, predominantly in Brazil, Africa, the Middle East, and South Asia. Schistosomiasis causes PAH in about 6.1% of those chronically infected and is particularly associated with the species Schistosoma mansoni. Treatment for schistosomiasis-associated PAH includes antihelminthic treatment, if active infection is present (although associated with little immediate benefit to the pulmonary hypertension), and then pharmacologic treatment with targeted pulmonary vascular therapies, including phosphodiesterase type 5 inhibitors and endothelin receptor antagonists. The pathophysiological mechanism by which this parasitic infection causes pulmonary hypertension is unknown but is unlikely to be simple mechanical obstruction of the pulmonary vasculature by parasite eggs. Preexisting hepatosplenic disease due to Schistosoma infection is likely important because of portopulmonary hypertension and/or because it allows egg embolization to the lung by portocaval shunts. Potential immune signaling originating in the periegg granulomas causing the pulmonary vascular disease includes the cytokines interleukin (IL)-4, IL-6, IL-13, and transforming growth factor β. Modulating these pathways may be possible targets for future therapy of schistosomiasis-associated PAH specifically, and study of this disease may provide novel insights into other inflammatory causes of PAH.

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“…Vascular SMCs and ECs isolated from these mice express only arginase II, whereas alveolar macrophages express both arginase isoforms. Deletion of arginase II in these animals decreased medial wall thickening of the pulmonary arteries and reduced the frequency of neovascularization of small pulmonary arteries (5).…”

Section: Discussionmentioning

confidence: 83%

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

Grasemann

Dhaliwal

Ivanovska

et al. 2015

American Journal of Physiology-Lung Cellular and Molecular Phys

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-Arginase is an enzyme that limits substrate L-arginine bioavailability for the production of nitric oxide by the nitric oxide synthases and produces L-ornithine, which is a precursor for collagen formation and tissue remodeling. We studied the pulmonary vascular effects of arginase inhibition in an established model of repeated systemic bleomycin sulfate administration in neonatal rats that results in pulmonary hypertension and lung injury mimicking the characteristics typical of bronchopulmonary dysplasia. We report that arginase expression is increased in the lungs of bleomycin-exposed neonatal rats and that treatment with the arginase inhibitor amino-2-borono-6-hexanoic acid prevented the bleomycininduced development of pulmonary hypertension and deposition of collagen. Arginase inhibition resulted in increased L-arginine and L-arginine bioavailability and increased pulmonary nitric oxide production. Arginase inhibition also normalized the expression of inducible nitric oxide synthase, and reduced bleomycin-induced nitrative stress while having no effect on bleomycin-induced inflammation. Our data suggest that arginase is a promising target for therapeutic interventions in neonates aimed at preventing lung vascular remodeling and pulmonary hypertension. nitric oxide; oxidative stress; chronic lung disease ARGINASES METABOLIZE L-ARGININE to form L-ornithine and urea. L-Ornithine is the precursor for the production of polyamines and collagen, which have been implicated in tissue repair and remodeling, respectively. Arginases also regulate nitric oxide (NO) production by controlling substrate L-arginine availability for NO synthases (NOSs) (46). There is accumulating evidence that arginase activity contributes to the development of pulmonary fibrosis and pulmonary hypertension (PHT) (9,14,25,29,32,63).PHT is a common complication of moderate-severe bronchopulmonary dysplasia (BPD), a chronic lung disease affecting extremely premature infants (6). The underlying pathogenesis of BPD is complex and multifactorial (39). Previous studies from our group have established a model of repeated systemic bleomycin injection in neonatal rats that results in lung injury mimicking characteristics typical of BPD. This model is a useful tool to help understand mechanisms contributing to lung development and remodeling (31) but also to study the effects of therapeutic interventions aimed at preventing lung parenchymal and vascular injury (31,50,56).The chemotherapeutic agent bleomycin sulfate causes a pulmonary inflammatory and fibrotic response in rodents when instilled as a single intratracheal dose (27) or by repeated intraperitoneal injection (3). Bleomycin-induced lung injury is characterized by induction of proinflammatory cytokines (18), influx of macrophages and other inflammatory cells (23), "emphysematous" lung morphology, and severe PHT (49, 60). Herein, we report that arginase expression is greatly increased in the lungs of bleomycin-exposed neonatal rats and that concomitant treatment with an arginase inhibitor, ami...

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IL-13 receptor α₂-arginase 2 pathway mediates IL-13-induced pulmonary hypertension

Cited by 46 publications

References 49 publications

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Schistosomiasis and the Pulmonary Vasculature (2013 Grover Conference Series)

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

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IL-13 receptor α2-arginase 2 pathway mediates IL-13-induced pulmonary hypertension

Cited by 46 publications

References 49 publications

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Resistin-Like Molecule α in Allergen-Induced Pulmonary Vascular Remodeling

Schistosomiasis and the Pulmonary Vasculature (2013 Grover Conference Series)

Arginase inhibition prevents bleomycin-induced pulmonary hypertension, vascular remodeling, and collagen deposition in neonatal rat lungs

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IL-13 receptor α₂-arginase 2 pathway mediates IL-13-induced pulmonary hypertension