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Stretch-Induced Alveolar Type II Cell Apoptosis

Role of Endogenous Bradykinin and PI3K-Akt Signaling

¹ Department of Respiratory Medicine, University of Leipzig, Leipzig, Germany

Correspondence and requests for reprints should be addressed to PD Dr. Stefan Hammerschmidt, Medizinische Universitätsklinik I, Pneumologie, Universität Leipzig, Johannisallee 32, 04103 Leipzig, Germany. E-mail: stefan.hammerschmidt{at}t-online.de

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. Rat ATII cells cultured on flexible membranes were subjected to cyclic stretch (40 cycles/min; 30% increase in surface area) and compared with static controls. Angiotensinogen, the bradykinin precursor T-kininogen, and bradykinin receptor expression were measured by RT-PCR; Angiotensin II and phosphoinositol 3 OH-kinase (PI3K) activity (as phospho-Akt) were measured by enzyme-linked immunosorbent assay; and Bcl-2 and Bcl-X_L were measured 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 and bradykinin supernatant concentration), and subsequently led to reduced PI3K activity and decreased concentrations of the anti-apoptotic proteins Bcl-2/Bcl-X_L. 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 to maintain oxygenation.

Key Words: mechanical stretch • apoptosis • PI3K • bradykinin

CLINICAL RELEVANCE Mechanical stretch impairs alveolar epithelial cell anti-apoptotic survival signaling via PI3K–Akt–BAD–Bcl-2/Bcl-XL. Restoration of PI3K activity prevents stretch-induced apoptosis and increases the tolerance of the cells to mechanical stretch.

 

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