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Critical Care Medicine:
doi: 10.1097/CCM.0b013e3181d4563f
Laboratory Investigations

Therapeutic accessibility of caspase-mediated cell death as a key pathomechanism in indirect acute lung injury*

Perl, Mario MD; Chung, Chun-Shiang PhD; Perl, Ulrike BS; Thakkar, Rajan MD; Lomas-Neira, Joanne PhD; Ayala, Alfred PhD

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Objective: Indirect acute lung injury is associated with high morbidity and mortality. However, the underlying pathophysiology is only marginally understood, and so far no pathophysiologic-based remedy exists. We hypothesized that apoptosis of lung epithelial cells is a pathophysiological relevant process in the development of indirect acute lung injury and that it should be accessible to a siRNA-based therapeutic intervention in vivo.

Design: Prospective, randomized, controlled animal study.

Setting: Basic science laboratory of a university affiliated level one trauma center.

Subjects: Male C3H/HeN mice, 8 wks old, n = 121.

Interventions: First, siRNA sequences to knock-down caspase-3 expression at a RNA and protein level were evaluated in vitro. Then, C3H/HeN mice were subjected to hemorrhagic shock, after which they received either a caspase-3 siRNA or a control/nonsense siRNA. Subsequently, they were then subjected to polymicrobial sepsis (induced by cecal ligation and puncture).

Measurements and Main Results: Twelve and 24 hrs after sepsis, increased lung epithelial apoptosis was observed, as evidenced by active caspase-3 Western blotting, caspase-3, TUNEL-, and M-30 immunohistochemistry. Hallmarks of acute lung injury, such as increased concentrations of pulmonary cytokines/chemokines, lung protein leakage, myeloperoxidase activity, and altered lung histology, were evident in response to these insults. The single intratracheal instillation of caspase-3 siRNA not only attenuated lung apoptosis and inflammation but also ameliorated the development of acute lung injury in treated mice. Most interestingly, this experimental therapeutic approach markedly improved 10-day survival of hemorrhaged septic mice.

Conclusions: Apoptosis of lung epithelial cells is a relevant pathomechanism in the development of hemorrhage-induced indirect septic acute lung injury, and caspase-3 appears to be a valuable therapeutic target accessible by siRNA treatment in vivo.

© 2010 by the Society of Critical Care Medicine and Lippincott Williams & Wilkins

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