Potential Contribution of Phenotypically Modulated Smooth Muscle Cells and Related Inflammation in the Development of Experimental Obstructive Pulmonary Vasculopathy in Rats

Abstract

We tested the hypothesis that phenotypically modulated smooth muscle cells (SMCs) and related inflammation are associated with the progression of experimental occlusive pulmonary vascular disease (PVD). Occlusive PVD was induced by combined exposure to a vascular endothelial growth factor receptor tyrosine kinase inhibitor Sugen 5416 and hypobaric hypoxia for 3 weeks in rats, which were then returned to ambient air. Hemodynamic, morphometric, and immunohistochemical studies, as well as gene expression analyses, were performed at 3, 5, 8, and 13 weeks after the initial treatment (n = 78). Experimental animals developed pulmonary hypertension and right ventricular hypertrophy, and exhibited a progressive increase in indices of PVD, including cellular intimal thickening and intimal fibrosis. Cellular intimal lesions comprised α smooth muscle actin (α SMA)+, SM1+, SM2+/-, vimentin+ immature SMCs that were covered by endothelial monolayers, while fibrous intimal lesions typically included α SMA+, SM1+, SM2+, vimentin+/- mature SMCs. Plexiform lesions comprised α SMA+, vimentin+, SM1-, SM2- myofibroblasts covered by endothelial monolayers. Immature SMC-rich intimal and plexiform lesions were proliferative and were infiltrated by macrophages, while fibrous intimal lesions were characterized by lower proliferative abilities and were infiltrated by few macrophages. Compared with controls, the number of perivascular macrophages was already higher at 3 weeks and progressively increased during the experimental period; gene expression of pulmonary hypertension-related inflammatory molecules, including IL6, MCP1, MMP9, cathepsin-S, and RANTES, was persistently or progressively up-regulated in lungs of experimental animals. We concluded that phenotypically modulated SMCs and related inflammation are potentially associated with the progression of experimental obstructive PVD.

Circulating microparticles in severe pulmonary arterial hypertension increase intercellular adhesion molecule-1 expression selectively in pulmonary artery endothelium

“…The rat model of PAH used in these studies exhibits hemodynamic and histological characteristics that worsen with time [ 19 ]. Additionally, inflammatory cells that accumulate around remodeled pulmonary vessels are dynamic in this animal model [ 20 ]. Prior studies have shown that at 8-weeks the hemodynamic profile of this model is severe PAH, the pulmonary vascular lesions range from concentric laminar smooth muscle to fully occluded and we confirmed ICAM-1 expression by staining control and late-stage PAH lung tissues (Additional file 1 : Figure S1).…”

Vascular endothelial growth factor receptor inhibition enhances chronic obstructive pulmonary disease picture in mice exposed to waterpipe smoke

“…VEGF also regulates growth and differentiation of type II pneumocytes, pointing to its critical role in the maintenance of "alveolar unit" normal functionality [43]. Blockade of such vital functions by SU could add to the alveolar damage induced by WPS exposure, enhancing the induction of a COPD picture, most notably by stimulating lung inflammatory cell infiltration, as reported by Otsuki et al [31].…”

Adverse effects of BMPR2 suppression in macrophages in animal models of pulmonary hypertension

“…Macrophages are a prominent component of the inflammatory infiltrates in experimental and clinical PAH 9,35,[71][72][73][74] and are thought to play a very important role in modulating the disease. 9,74 Macrophage depletion or inactivation is shown to prevent experimentally induced hypoxic PH and portopulmonary hypertension.…”