Abrogation of bleomycin-induced epithelial apoptosis and lung fibrosis by captopril or by a caspase inhibitor

Abstract

Angiotensin-converting enzyme is involved in apoptosis of alveolar epithelial cells (Wang R, Zagariya A, Ang E, Ibarra-Sunga O, and Uhal BD. Am J Physiol Lung Cell Mol Physiol 277: L1245-L1250, 1999). This study tested the ability of the angiotensin-converting enzyme inhibitor captopril or the caspase inhibitor Z-Val-Ala-Asp-fluoromethylketone (ZVAD-fmk) to block alveolar epithelial cell apoptosis and lung fibrosis in vivo in response to bleomycin (Bleo). Male Wistar rats received 8 U/kg of Bleo (bleomycin sulfate) or vehicle intratracheally. Subgroups of Bleo-treated rats received captopril, ZVAD-fmk, or vehicle alone. Lung collagen was assessed by picrosirius red or hydroxyproline assay at 1, 7, and 14 days post-Bleo, and apoptosis was detected by in situ end labeling (ISEL). Bleo increased alveolar septal and peribronchial collagen by 100 and 133%, respectively (both P < 0.01), by day 14 but not earlier. In contrast, ISEL was increased in alveolar and airway cells at all time points. Captopril or ZVAD-fmk inhibited collagen accumulation by 91 and 85%, respectively (P < 0. 01). Both agents also inhibited ISEL in alveoli by 99 and 81% and in airways by 67 and 63%, respectively. These data suggest that the efficacy of captopril to inhibit experimental lung fibrogenesis is related to inhibition of apoptosis. They also demonstrate the antifibrotic potential of a caspase inhibitor.

Bleomycin induces the extrinsic apoptotic pathway in pulmonary endothelial cells

“…Apoptosis of pulmonary endothelial and epithelial cell plays an important role in the initiation and progression of pulmonary fibrosis (2,9,11,32), and the mechanism of bleomycininduced apoptosis in lung cells has been a critical topic for pulmonary fibrosis research (17,18,28,30). The major finding of this study is that, in primary pulmonary endothelial cells, bleomycin induces early activation of the extrinsic apoptotic pathway, but not of the intrinsic apoptotic pathway.…”

Deranged fatty acid composition causes pulmonary fibrosis in Elovl6-deficient mice

“…We demonstrated that Elovl6 deficiency resulted in exacerbation of pulmonary fibrosis in mice when they are exposed to BLM. A number of evidence established that BLM induced apoptosis in the alveolar epithelial and endothelial cells [25][26][27] , which has a key role in the initiation and progression of pulmonary fibrosis 28 . Indeed, we found the induction of apoptosis and caspase 3 activation in the lung from Elovl6 À / À mice, and confirmed them in Elovl6-kockdown LA-4 cells.…”

Angiotensin II in apoptotic lung injury: potential role in meconium aspiration syndrome

“…37 Blockade of apoptosis by either the angiotensin-converting enzyme (ACE) inhibitor captopril, caspase inhibition or the forced expression of p21 in lung epithelial cells exerted antifibrotic effects in animal models. 36,38,39 Together, these data suggested that the fibrotic response is secondary to the apoptotic death of epithelial cells in the lung. The death receptor Fas was found to be expressed in AECs within the lungs of IPF patients and circulating levels of its ligand FasL correlated with disease activity.…”

“…Apoptosis of alveolar epithelial cells (AECs) is found in patients with idiopathic PF (IPF) and in animal models of the disease. [34][35][36] The epithelial apoptosis colocalizes with myofibroblasts where collagen deposition is severe. 37 Blockade of apoptosis by either the angiotensin-converting enzyme (ACE) inhibitor captopril, caspase inhibition or the forced expression of p21 in lung epithelial cells exerted antifibrotic effects in animal models.…”