Captopril inhibits apoptosis in human lung epithelial cells: a potential antifibrotic mechanism

Abstract

The angiotensin-converting enzyme inhibitor captopril has been shown to inhibit fibrogenesis in the lung, but the mechanisms underlying this action are unclear. Apoptosis of lung epithelial cells is believed to be involved in the pathogenesis of pulmonary fibrosis. For these reasons, we studied the effect of captopril on Fas-induced apoptosis in a human lung epithelial cell line. Monoclonal antibodies that activate the Fas receptor induced epithelial cell apoptosis as detected by chromatin condensation, nuclear fragmentation, DNA fragmentation, and increased activities of caspase-1 and -3. Apoptosis was not induced by isotype-matched nonimmune mouse immunoglobulins or nonactivating anti-Fas monoclonal antibodies. When applied simultaneously with anti-Fas antibodies, 50 ng/ml of captopril completely abrogated apoptotic indexes based on morphology, DNA fragmentation, and inducible caspase-1 activity and significantly decreased the inducible activity of caspase-3. Inhibition of apoptosis by captopril was concentration dependent, with an IC50 of 70 pg/ml. These data suggest that the inhibitory actions of captopril on pulmonary fibrosis may be related to prevention of lung epithelial cell apoptosis.

Reduced Severity of a Mouse Colitis Model with Angiotensin Converting Enzyme Inhibition

“…Small intestinal epithelial apoptosis is elevated in a mouse model of short-bowel syndrome; and ACE-I reduces apoptosis in this setting (22). Extensive studies in alveolar epithelial cells have demonstrated that ACE activity is necessary for apoptosis in these cells (20,(34)(35). Angiotensin II, produced by ACE, induces apoptosis of pulmonary alveolar epithelial cells in a dose-dependent manner (34).…”

“…However, a number of other ACE-inhibitors have also been shown to inhibit apoptosis in other tissues, including enalapril (32), quinaprilat (36), and captopril (35), as well as other inhibitors of components of the ACE/Angiotensin signaling cascade, such as angiotensin receptor blockers (30,40).…”

“…Studies using pharmacologic ACE inhibition (ACE-I) have shown that ACE-I significantly reduces apoptosis in pulmonary and cardiac cells (31)(32)(33)(34); and this reduction of apoptosis exhibits a concentration dependent effect (34). In addition, investigators have shown that Ang II is required for the induction of apoptosis in alveolar epithelial cells and cardiac myocytes (31)(32)(33)(34)(35)(36). The production of Ang II is precisely what ACE-I prevents.…”

The effect of captopril on brain apoptosis after burn injury in rats

“…It is known that apoptosis plays an important role in tissue remodelling in pathological conditions. Captopril has recently been found to inhibit Fas-induced apoptosis in human activated T cells (7) and lung epithelial cells (41). Moreover, the neuroprotective effects of ACE inhibitors have been verified in histological studies (45).…”

Elucidating the causes and examining the latest clinical findings in pulmonary fibrosis: recent progress and future objectives

“…Angiotensin receptor blockade represents another possible therapeutic approach to selective apoptosis and derives from evidence that angiotensin II is an important mediator of apoptosis of alveolar epithelial cells [9] and other pro-fibrogenic actions [10]. Experimental studies have shown that administration of an angiotensin-1 receptor antagonist can attenuate pulmonary fibrosis in vivo [11], while also inhibiting Fas-induced apoptosis in cultured human lung cells [12].…”