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

Fan, Chunling; Meuchel, Lucas W.; Su, Qingning; Angelini, Daniel J.; Zhang, Ailan; Cheadle, Chris; Kolosova, Irina; Makarevich, Oleg; Yamaji-Kegan, Kazuyo; Rothenberg, Marc E.; Johns, Roger A.

doi:10.1165/rcmb.2014-0322oc

Cited by 20 publications

(21 citation statements)

References 41 publications

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“…In another study of repeated intratracheal instillations of S. chartarum, goblet cell metaplasia was observed after seven exposures, but not after a single exposure, indicative of airway remodeling after S. chartarum exposure (25). In agreement with Fan and colleagues, retnla was increased with arterial remodeling, together with asthma pathogenesis and tissue remodeling-associated proteins (32). These proteins and respective genes were significantly increased after both viable S. chartarum exposures compared with air-only and HIC controls, as well as at an earlier time point in strain A-exposed versus strain B-exposed mice.…”

Section: Discussionsupporting

confidence: 75%

Inhalation of Stachybotrys chartarum Fragments Induces Pulmonary Arterial Remodeling

Croston

Lemons

Barnes

et al. 2020

Am J Respir Cell Mol Biol

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Stachybotrys chartarum is a fungal contaminant within the built environment and a respiratory health concern in the United States. The objective of this study was to characterize the mechanisms influencing pulmonary immune responses to repeatedly inhaled S. chartarum. Groups of B6C3F1/N mice repeatedly inhaled viable trichothecene-producing S. chartarum conidia (strain A or strain B), heat-inactivated conidia, or high-efficiency particulate absolute-filtered air twice per week for 4 and 13 weeks. Strain A was found to produce higher amounts of respirable fragments than strain B. Lung tissue, serum, and BAL fluid were collected at 24 and 48 hours after final exposure and processed for histology, flow cytometry, and RNA and proteomic analyses. At 4 weeks after exposure, a T-helper cell type 2-mediated response was observed. After 13 weeks, a mixed T-cell response was observed after exposure to strain A compared with a T-helper cell type

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Section: Discussionsupporting

confidence: 75%

Inhalation of Stachybotrys chartarum Fragments Induces Pulmonary Arterial Remodeling

Croston

Lemons

Barnes

et al. 2020

Am J Respir Cell Mol Biol

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“…4 Furthermore, we have shown that IL-17 expression in the lung is significantly suppressed in global HIMF/RELMα knockout mice as compared with that in wild-type mice during allergic inflammation. 47 It is reasonable to speculate that an increase in IL-6 in lung resident cells in response to HIMF can induce a sequential Th2/Th17 response. In accordance with our results, a recent study by Jang et al 48 showed that hRETN preferentially binds myeloid cells such as monocytes and macrophages in the lung during parasitic infections, and promotes proinflammatory cytokine expression.…”

Section: Discussionmentioning

confidence: 99%

Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)–Induced Pulmonary Hypertension

Johns¹,

Takimoto²,

Meuchel³

et al. 2016

ATVB

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Objective Pulmonary hypertension (PH) is characterized by progressive elevation of pulmonary vascular resistance, right ventricular failure, and ultimately death. We have shown that in rodents, hypoxia-induced mitogenic factor (HIMF; also known as FIZZ1 or RELMα) causes PH by initiating lung vascular inflammation. We hypothesized that hypoxia-inducible factor-1 (HIF-1) is a critical downstream signal mediator of HIMF during PH development. Approach and Results In this study, we compared the degree of HIMF-induced pulmonary vascular remodeling and PH development in wild-type (HIF-1α+/+) and HIF-1α heterozygous null (HIF-1α+/−) mice. HIMF-induced PH was significantly diminished in HIF-1α+/− mice and was accompanied by a dysregulated VEGF-A–VEGF receptor 2 pathway. HIF-1α was critical for bone marrow-derived cell migration and vascular tube formation in response to HIMF. Furthermore, HIMF and its human homolog, resistin-like molecule-β (RELMβ), significantly increased IL-6 in macrophages and lung resident cells through a mechanism dependent on HIF-1α and, at least to some extent, on nuclear factor κB. Conclusions Our results suggest that HIF-1α is a critical downstream transcription factor for HIMF-induced pulmonary vascular remodeling and PH development. Importantly, both HIMF and human RELMβ significantly increased IL-6 in lung resident cells and increased perivascular accumulation of IL-6–expressing macrophages in the lungs of mice. These data suggest that HIMF can induce HIF-1, VEGF-A, and interleukin-6, which are critical mediators of both hypoxic inflammation and PH pathophysiology.

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“…Resistin-like molecule (RELM)-α, a striking downstream product of the IL-4 and IL-13 signaling pathways in allergen-and parasite-associated Th2 responses, is overexpressed in the lungs regulated by Th2-and IL-13-mediated inflammation and hypoxia. RELM-α-knockout mice inhibited pulmonary vascular remodeling and the increase of pulmonary pressure and cardiac hypertrophy, thus leading to less vessel muscularization, less perivascular inflammation and reduced medial thickness of intraalveolar vessels [53]. It was observed that the expressions of RELM-α, were increased associated with an enhanced IL-13 signaling in infected wild-type and IL-13Rα2 −/− but not IL-13Rα1 −/− mice.…”

Section: Treatmentmentioning

confidence: 97%

Interleukin-13 in the pathogenesis of pulmonary artery hypertension

Yuan

2019

Journal of Laboratory Medicine

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Background Interleukin (IL)-13 is a regulatory factor of tissue remodeling and is involved in the pathogenesis of pulmonary artery hypertension (PAH). However, the implications of IL-13 in PAH remains uncertain. This article aims to describe the current knowledge on production and function of IL-13 and its receptors in the mechanisms of PAH. Content The study materials of this article were based on comprehensive literature retrieval of publications of IL-13 in PAH. These study materials were carefully reviewed, analyzed and discussed. Summary IL-13 levels in blood and lung tissue were elevated in both animal models of PAH and patients with PAH in comparison to non-PAH controls. Types I and II IL-13 receptors participate in pulmonary artery remodeling through signal transducer and activator of transcription (STAT)6 or through phosphatidylinositol 3-kinase (PI3K), STAT3 and mitogen activated protein kinase (MAPK) pathways. Oxidant, arginase 2 (Arg2) and hypoxia-inducible factor 1α are involved in the proliferation of pulmonary artery smooth muscle cells. Outlook Types I and II IL-13 receptors play an important role in the IL-13 signaling by STAT6 via Janus kinase kinases, and by PI3K, STAT3 and MAPK pathways, respectively. Alternative pathways, including oxidant, Arg2 and hypoxia-inducible factor 1α might be also involved in the pathological process of PAH development. Investigational therapies by inflammatory suppression or thrombolytic and anticoagulant agents could inhibit intimal hyperplasia of the pulmonary arteries and suppress pulmonary vasculature remodeling. Drug research and development oriented by this hypothesis would confer benefits to the treatment of PAH.

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

Cited by 20 publications

References 41 publications

Inhalation of Stachybotrys chartarum Fragments Induces Pulmonary Arterial Remodeling

Inhalation of Stachybotrys chartarum Fragments Induces Pulmonary Arterial Remodeling

Hypoxia-Inducible Factor 1α Is a Critical Downstream Mediator for Hypoxia-Induced Mitogenic Factor (FIZZ1/RELMα)–Induced Pulmonary Hypertension

Interleukin-13 in the pathogenesis of pulmonary artery hypertension

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