Chymase: a multifunctional player in pulmonary hypertension associated with lung fibrosis

Abstract

Limited literature sources implicate mast-cell mediator chymase in the pathologies of pulmonary hypertension and pulmonary fibrosis. However, there is no evidence on the contribution of chymase to the development of pulmonary hypertension associated with lung fibrosis, which is an important medical condition linked with increased mortality of patients who already suffer from a life-threatening interstitial lung disease.The aim of this study was to investigate the role of chymase in this particular pulmonary hypertension form, by using a bleomycin-induced pulmonary hypertension model.Chymase inhibition resulted in attenuation of pulmonary hypertension and pulmonary fibrosis, as evident from improved haemodynamics, decreased right ventricular remodelling/hypertrophy, pulmonary vascular remodelling and lung fibrosis. These beneficial effects were associated with a strong tendency of reduction in mast cell number and activity, and significantly diminished chymase expression levels. Mechanistically, chymase inhibition led to attenuation of transforming growth factor β1 and matrix-metalloproteinase-2 contents in the lungs. Furthermore, chymase inhibition prevented big endothelin-1-induced vasoconstriction of the pulmonary arteries.Therefore, chymase plays a role in the pathogenesis of pulmonary hypertension associated with pulmonary fibrosis and may represent a promising therapeutic target. In addition, this study may provide valuable insights on the contribution of chymase in the pulmonary hypertension context, in general, regardless of the pulmonary hypertension form. @ERSpublications Chymase plays an important role in pathology of pulmonary hypertension associated with lung fibrosis

Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

“…Paraffin-embedded human lung tissues were subjected to immunohistochemistry as previously described (Kosanovic et al, 2015) using polyclonal anti-FGF10 (Antibodies-online, ABIN360398, 1:30), monoclonal anti-ACTA2 (Sigma-Aldrich, 1:900) and polyclonal anti-vWF antibodies (Dako, 1:900). Masson's trichrome and hematoxylin/eosin stainings were performed according to standard procedures.…”

Two-Way Conversion between Lipogenic and Myogenic Fibroblastic Phenotypes Marks the Progression and Resolution of Lung Fibrosis

“…Paraffin-embedded human lung tissues were subjected to immunohistochemistry as previously described (Kosanovic et al, 2015) using polyclonal anti-FGF10 (Antibodiesonline, ABIN360398, 1:30), monoclonal anti-ACTA2 (Sigma-Aldrich, 1:900) and polyclonal anti-vWF antibodies (Dako, 1:900). Masson's trichrome and hematoxylin/eosin stainings were performed according to standard procedures.…”

The controversial role of mast cells in fibrosis

“…Based on the hypothesis that chymase contributes to the development of fibrotic lesions, investigators have sought to interfere with fibrosis by administrating various chymase inhibitors. Indeed, the chymase inhibitors SUN‐C8077, BCEAB and NK3201 reduced bleomycin‐induced lung fibrosis in separate studies . Mechanistically, it was shown that chymase inhibition led to a decrease in the content of TGFβ and MMP2 in the lungs, and it was demonstrated that chymase inhibition prevented effects of endothelin‐1.…”

“…Indeed, the chymase inhibitors SUN-C8077, BCEAB and NK3201 reduced bleomycininduced lung fibrosis in separate studies. [227][228][229] Mechanistically, it was shown that chymase inhibition led to a decrease in the content of TGFβ and MMP2 in the lungs, and it was demonstrated that chymase inhibition prevented effects of endothelin-1. The latter observation is thus in agreement with a previous study where chymase was shown to be pivotal for the conversion of Big-endothelin-1 to endothelin-1.…”