Apoptosis of alveolar type II (ATII) cells in response to high amplitude mechanical stretch represents an important mechanism of ventilation-induced lung injury. Previously, it was demonstrated in an in vitro model that stretch induced ATII cell apoptosis was prevented by Angiotensin converting enzyme (ACE) inhibitors. This study investigates the mechanism by which ACE inhibitors prevent stretch-induced apoptosis and elucidates the role of Bradykinin as an endogenous anti apoptotic factor. Methods: Rat ATII cells cultured on flexible membranes were subjected to cyclic stretch (40/min; 30% increase in surface area) and compared with static controls. Angiotensinogen, the Bradykinin precursor T-kininogen, Bradykinin receptor expression were measured by RT PCR, Angiotensin II, phosphoinositol 3 OH-kinase (PI3K) activity (as phospho-Akt) by ELISA, Bcl-2 and Bcl-XL by western blot. Stretch did not influence Angiotensinogen expression or induce Angiotensin II generation. The Angiotensin II receptor antagonist Saralasin did not prevent stretch-induced apoptosis, whereas ACE inhibitors did. Stretch reduced ATII cell Bradykinin release (T-kininogen expression Bradykinin supernatant concentration), and subsequently led to reduced PI3K activity and decreased concentrations of the anti-apoptotic proteins Bcl-2/Bcl-XL. Bradykinin substitution or addition of keratinocyte or hepatocyte growth factor prevented stretch-induced decrease in PI3K activity and Bcl-2/Bcl-X_L and reduced stretch-induced apoptosis. Mechanical stretch impairs a constitutively expressed, autocrine anti-apoptotic ATII cell survival signal involving Bradykinin-mediated stimulation of the PI3K-Akt-Bcl-2/Bcl-X_L pathway. Restoration of this pathway prevents stretch-induced apoptosis. This may be beneficial when mechanical ventilation cannot completely avoid alveolar overdistension in order to maintain oxygenation.