Bronchial Smooth Muscle Cells of Asthmatics Promote Angiogenesis through Elevated Secretion of CXC-Chemokines (ENA-78, GRO-α, and IL-8)

Keglowich, Laura; Roth, Michael; Philippova, Maria; Resink, Thérèse J.; Tjin, Gavin; Oliver, Brian G.; Lardinois, Didier; Dessus-Babus, Sophie; Gosens, Reinoud; Hostettler, Katrin; Tamm, Michael; Borger, Pieter

doi:10.1371/journal.pone.0081494

Cited by 36 publications

(16 citation statements)

References 49 publications

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“…ENA‐78 (epithelial neutrophil‐activating peptide 78 or CXCL5) is a small neutrophil chemo‐attractant cytokine being normally produced as a result of inflammatory stimulation. ENA‐78 was also reported to have potential in regulation of angiogenesis . This finding is consistent with the previous data regarding TCs involvement in (neo)angiogenesis in heart .…”

Section: Discussionsupporting

confidence: 91%

Skin telocytes versus fibroblasts: two distinct dermal cell populations

Kang

Zhu

Zheng

et al. 2015

J Cellular Molecular Medi

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It is already accepted that telocytes (TCs) represent a new type of interstitial cells in human dermis. In normal skin, TCs have particular spatial relations with different dermal structures such as blood vessels, hair follicles, arrector pili muscles or segments of sebaceous and/or eccrine sweat glands. The distribution and the density of TCs is affected in various skin pathological conditions. Previous studies mentioned the particular (ultra)structure of TCs and also their immunophenotype, miR imprint or proteome, genome or secretome features. As fibroblast is the most common intersitital cell (also in human dermis), a dedicated comparison between human skin TCs and fibroblasts (Fbs) was required to be performed. In this study, using different techniques, we document several points of difference between human dermis TCs and Fbs. By transmission electron microscopy (TEM) and scanning electron microscopy (SEM), we demonstrated TCs with their hallmark cellular prolongations – telopodes. Thus, we showed their ultrastructural distinctiveness from Fbs. By RayBio Human Cytokine Antibody Array V analyses performed on the supernatant from separately cultured TCs and Fbs, we detected the cytokine profile of both cell types, individually. Two of 79 detected cytokines – epithelial-derived neutrophil-activating peptide 78 and granulocyte chemotactic protein-2 – were 1.5 times higher in the supernatant of TCs (comparing with Fbs). On the other hand, 37 cytokines were at least 1.5 higher in Fbs supernatant (comparing with TCs), and among them six cytokines – interleukin 5, monocyte chemotactic protein-3 (MCP-3), MCP-4, macrophage inflammatory protein-3, angiogenin, thrombopoietin – being 9.5 times higher (results also confirmed by ELISA testing). In summary, using different techniques, we showed that human dermal TCs and Fbs are different in terms of ultrastructure and cytokine profile.

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Section: Discussionsupporting

confidence: 91%

Skin telocytes versus fibroblasts: two distinct dermal cell populations

Kang

Zhu

Zheng

et al. 2015

J Cellular Molecular Medi

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“…Previously, we showed that BSMC isolated from asthma patients exhibit increased angiogenic potential, which associated with increased productions of CXCR2 ligands (ENA78, GRO-a and IL-8) and VEGF [37]. Our present study showed that hypoxia predominantly induced VEGF and IL-6, whereas IL-8 was only 2fold increased and ENA-78 not affected.…”

Section: Discussionsupporting

confidence: 57%

Hypoxia Exerts Dualistic Effects on Inflammatory and Proliferative Responses of Healthy and Asthmatic Primary Human Bronchial Smooth Muscle Cells

et al. 2014

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BackgroundFor oxygen supply, airway wall cells depend on diffusion though the basement membrane, as well as on delivery by micro-vessels. In the asthmatic lung, local hypoxic conditions may occur due to increased thickness and altered composition of the basement membrane, as well as due to edema of the inflamed airway wall.ObjectiveIn our study we investigated the effect of hypoxia on proliferation and pro-inflammatory and pro-angiogenic parameter production by human bronchial smooth muscle cells (BSMC). Furthermore, conditioned media of hypoxia-exposed BSMC was tested for its ability to induce sprout outgrowth from endothelial cells spheroids.MethodsBSMC were cultured in RPMI1640 (5% FCS) under normoxic (21% O2) and hypoxic (1% and 5% O2) conditions. Proliferation was determined by cell count and Western blot analysis for cyclin E and Proliferating Cell Nuclear Antigen (PCNA). Secretion of IL-6, IL-8, ENA-78 and VEGF-A was analyzed by ELISA. BSMC conditioned medium was tested for its angiogenic capacity by endothelial cell (EC)-spheroid in vitro angiogenesis assay.ResultsProliferation of BSMC obtained from asthmatic and non-asthmatic patients was significantly reduced in the presence of 1% O2, whereas 5% O2 reduced proliferation of asthmatic BSMC only. Hypoxia induced HIF-1α expression in asthmatic and non-asthmatic BSMC, which coincided with significantly increased release of IL-6, IL-8 and VEGF-A, but not ENA-78. Finally, endothelial sprout outgrowth from EC spheroids was increased when exposed to hypoxia conditioned BSMC medium.ConclusionHypoxia had dualistic effects on proliferative and inflammatory responses of asthmatic and non-asthmatic BSMC. First, hypoxia reduced BSMC proliferation. Second, hypoxia induced a pro-inflammatory, pro-angiogenic response. BSMC and EC may thus be promising new targets to counteract and/or alleviate airway wall remodeling.

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“…However, attempts to delve further into the mechanisms of airway angiogenesis and the pathophysiology of angiogenic vessels in asthmatic subjects are limited. Culture medium from airway smooth muscle biopsied from asthmatics and grown in vitro has been shown to cause endothelial cell tube formation in assay systems [25,26]. These studies suggest that a number of common growth factors such as VEGF-A, angiopoetin, IL-8 are all capable of stimulating microvessel growth in vitro.…”

Section: Discussionmentioning

confidence: 99%

Angiogenesis and airway reactivity in asthmatic Brown Norway rats

et al. 2014

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Expanded and aberrant bronchial vascularity, a prominent feature of the chronic asthmatic airway, might explain persistent airway wall edema and sustained leukocyte recruitment. Since it is well established that there are causal relationships between exposure to house dust mite (HDM) and the development of asthma, determining the effects of HDM in rats, mammals with a bronchial vasculature similar to humans, provides an opportunity to study the effects of bronchial angiogenesis on airway function directly. We studied rats exposed bi-weekly to HDM (Der p 1; 50μg/challenge by intranasal aspiration, 1,2,3 wks) and measured the time course of appearance of increased blood vessels within the airway wall. Results demonstrated that within 3 wks of HDM exposure, the number of vessels counted within airway walls of bronchial airways (0.5–3 mm perimeter) increased significantly. These vascular changes were accompanied by increased airway responsiveness to methacholine. A shorter exposure regimen (2 wks of bi-weekly exposure) was insufficient to cause a significant increase in functional vessels or reactivity. Yet, 19F/1H MR imaging at 3T following αvβ3-targeted perfluorocarbon nanoparticle infusion revealed a significant increase in 19F signal in rat airways after 2 wks of bi-weekly HDM, suggesting earlier activation of the process of neovascularization. Although many antigen-induced mouse models exist, mice lack a bronchial vasculature, and consequently lack the requisite human parallels to study bronchial edema. Overall our results provide an important new model to study the impact of bronchial angiogenesis on chronic inflammation and airways hyperreactivity.

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Bronchial Smooth Muscle Cells of Asthmatics Promote Angiogenesis through Elevated Secretion of CXC-Chemokines (ENA-78, GRO-α, and IL-8)

Cited by 36 publications

References 49 publications

Skin telocytes versus fibroblasts: two distinct dermal cell populations

Skin telocytes versus fibroblasts: two distinct dermal cell populations

Hypoxia Exerts Dualistic Effects on Inflammatory and Proliferative Responses of Healthy and Asthmatic Primary Human Bronchial Smooth Muscle Cells

Angiogenesis and airway reactivity in asthmatic Brown Norway rats

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