Acute and chronic hypoxia as well as 7‐day recovery from chronic hypoxia affects the distribution of pulmonary mast cells and their MMP‐13 expression in rats

Abstract

Chronic hypoxia results in pulmonary hypertension due to vasoconstriction and structural remodelling of peripheral lung blood vessels. We hypothesize that vascular remodelling is initiated in the walls of prealveolar pulmonary arteries by collagenolytic metalloproteinases (MMP) released from activated mast cells. Distribution of mast cells and their expression of interstitial collagenase, MMP-13, in lung conduit, small muscular, and prealveolar arteries was determined quantitatively in rats exposed for 4 and 20 days to hypoxia as well as after 7-day recovery from 20-day hypoxia (10% O2). Mast cells were identified using Toluidine Blue staining, and MMP-13 expression was detected using monoclonal antibody. After 4, but not after 20 days of hypoxia, a significant increase in the number of mast cells and their MMP-13 expression was found within walls of prealveolar arteries. In rats exposed for 20 days, MMP-13 positive mast cells accumulated within the walls of conduit arteries and subpleurally. In recovered rats, MMP-13 positive mast cells gathered at the prealveolar arterial level as well as in the walls of small muscular arteries; these mast cells stayed also in the conduit part of the pulmonary vasculature. These data support the hypothesis that perivascular pulmonary mast cells contribute to the vascular remodelling in hypoxic pulmonary hypertension in rats by releasing interstitial collagenase.

Protection from adverse myocardial remodeling secondary to chronic volume overload in mast cell deficient rats

“…It should be remembered, however, that several other mast cell products, including tryptase and chymase, are also capable of activating MMPs [29][30][31]. Furthermore, while not yet determined in cardiac mast cells, non-cardiac mast cells have been shown to produce various MMPs including MMP-1 [32], -2 [33], -9 [33,34], and -13 [35], as well as ADAM-9, -10 and -17 [33]. It is possible that cardiac mast cells may also produce some or all of these MMPs.…”

Immune Dysregulation and Endothelial Dysfunction in Pulmonary Arterial Hypertension

“…70 How mast cells may contribute to PAH pathophysiology is by guest on May 12, 2018 http://circ.ahajournals.org/ Downloaded from not clear, but proposed mechanisms include direct vasoactive effects and stimulation of remodeling by increased production of matrix metalloproteinases. 71 More proof of altered immune responses in PAH comes from the potential role of T lymphocytes, particularly Tregs, in PAH pathogenesis. Taraseviciene-Stewart and coauthors 72 showed that, in contrast to vascular endothelial growth factor receptor blocker SU5416-treated euthymic rats that develop severe PH only in combination with chronic hypoxia, athymic nude rats developed severe PH and pulmonary vascular remodeling at normoxic conditions.…”

Matrix metalloproteinases and their inhibitors in pulmonary hypertension

“…Release of MMP-13 by perivascular mast cells in hypoxic PH [112] MMP-2, MMP-9 and MMP-13 Chronic hypoxic exposure increases the expression of gelatinase and rat interstitial collagenase, MMP-13, in peripheral pulmonary arteries [113] MMP-2 and MMP-9 Time-dependent increase in gelatinase MMP-2 activity was associated with the progression of hypoxic PH in pulmonary vessels [110] Collagenase and TIMP-1 Mast cell-derived collagenase contributes to collagen breakdown in pulmonary arteries during early recovery from hypoxia and plays a role in restoration of vascular architecture elastin preceding the development of vascular changes. Elastin peptides generated by serine elastases and/or MMPs stimulate the production of the matrix glycoprotein fibronectin, which changes SMCs from a contractile to a migratory phenotype [123].…”