This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Perl, M. Articles by Ayala, A. Search for Related Content PubMed PubMed Citation Articles by Perl, M. Articles by Ayala, A.

(American Journal of Pathology. 2005;167:1545-1559.)
© 2005 American Society for Investigative Pathology

Silencing of Fas, but Not Caspase-8, in Lung Epithelial Cells Ameliorates Pulmonary Apoptosis, Inflammation, and Neutrophil Influx after Hemorrhagic Shock and Sepsis

Mario Perl^*, Chun-Shiang Chung^*, Joanne Lomas-Neira, Tina-Marie Rachel^*, Walter L. Biffl, William G. Cioffi and Alfred Ayala^*

From the Shock-Trauma Research Laboratories,^* Division of Surgical Research, and the Department of Surgery, Rhode Island Hospital and Brown University School of Medicine, Providence; and the Department of Cell and Molecular Biology, University of Rhode Island, Kingston, Rhode Island

Apoptosis and inflammation play an important role in the pathogenesis of direct/pulmonary acute lung injury (ALI). However, the role of the Fas receptor-driven apoptotic pathway in indirect/nonpulmonary ALI is virtually unstudied. We hypothesized that if Fas or caspase-8 plays a role in the induction of indirect ALI, their local silencing using small interfering RNA (siRNA) should be protective in hemorrhage-induced septic ALI. Initially, as a proof of principle, green fluorescent protein-siRNA was administered intratracheally into transgenic mice overexpressing green fluorescent protein. Twenty-four hours after siRNA delivery, lung sections revealed a significant decrease in green fluorescence. Intratracheally administered Cy-5-labeled Fas-siRNA localized primarily in pulmonary epithelial cells. Intratracheal instillation of siRNA did not induce lung inflammation via toll-like receptor or protein kinase PKR pathways as assessed by lung tissue interferon-, tumor necrosis factor-, and interleukin (IL)-6 levels. Mice subjected to hemorrhagic shock and sepsis received either Fas-, caspase-8-, or control-siRNA intratracheally 4 hours after hemorrhage. Fas- or caspase-8-siRNA significantly reduced lung tissue Fas or caspase-8 mRNA, respectively. Only Fas-siRNA markedly diminished lung tissue tumor necrosis factor-, IL-6, IL-10, interferon-, IL-12, and caspase-3 activity. Fas-siRNA also preserved alveolar architecture and reduced lung neutrophil infiltration and pulmonary epithelial apoptosis. These data indicate the pathophysiological significance of Fas activation in nonpulmonary/shock-induced ALI and the feasibility of intrapulmonary administration of anti-apoptotic siRNA in vivo.

This article has been cited by other articles:

				N. Matsuda, S. Yamamoto, K.-i. Takano, S.-i. Kageyama, Y. Kurobe, Y. Yoshihara, Y. Takano, and Y. Hattori Silencing of Fas-associated Death Domain Protects Mice from Septic Lung Inflammation and Apoptosis Am. J. Respir. Crit. Care Med., May 1, 2009; 179(9): 806 - 815. [Abstract] [Full Text] [PDF]

				D. Barlos, E. A. Deitch, A. C. Watkins, F. J. Caputo, Q. Lu, B. Abungu, I. Colorado, D.-Z. Xu, and R. Feinman Trauma-hemorrhagic shock-induced pulmonary epithelial and endothelial cell injury utilizes different programmed cell death signaling pathways Am J Physiol Lung Cell Mol Physiol, March 1, 2009; 296(3): L404 - L417. [Abstract] [Full Text] [PDF]

				C. K. Hu, F. Venet, D. S. Heffernan, Y. L. Wang, B. Horner, X. Huang, C.-S. Chung, S. H. Gregory, and A. Ayala The Role of Hepatic Invariant NKT Cells in Systemic/Local Inflammation and Mortality during Polymicrobial Septic Shock J. Immunol., February 15, 2009; 182(4): 2467 - 2475. [Abstract] [Full Text] [PDF]

				R. A. Bem, A. W. Farnand, V. Wong, A. Koski, M. E. Rosenfeld, N. van Rooijen, C. W. Frevert, T. R. Martin, and G. Matute-Bello Depletion of resident alveolar macrophages does not prevent Fas-mediated lung injury in mice Am J Physiol Lung Cell Mol Physiol, August 1, 2008; 295(2): L314 - L325. [Abstract] [Full Text] [PDF]

				M. E. De Paepe, S. Gundavarapu, U. Tantravahi, J. R. Pepperell, S. A. Haley, F. I. Luks, and Q. Mao Fas-Ligand-Induced Apoptosis of Respiratory Epithelial Cells Causes Disruption of Postcanalicular Alveolar Development Am. J. Pathol., July 1, 2008; 173(1): 42 - 56. [Abstract] [Full Text] [PDF]

				V. Nomellini, D. E. Faunce, C. R. Gomez, and E. J. Kovacs An age-associated increase in pulmonary inflammation after burn injury is abrogated by CXCR2 inhibition J. Leukoc. Biol., June 1, 2008; 83(6): 1493 - 1501. [Abstract] [Full Text] [PDF]

				M. Perl, C.-S. Chung, U. Perl, J. Lomas-Neira, M. de Paepe, W. G. Cioffi, and A. Ayala Fas-induced Pulmonary Apoptosis and Inflammation during Indirect Acute Lung Injury Am. J. Respir. Crit. Care Med., September 15, 2007; 176(6): 591 - 601. [Abstract] [Full Text] [PDF]

				X. Li, E. J. Kovacs, M. G. Schwacha, I. H. Chaudry, and M. A. Choudhry Acute alcohol intoxication increases interleukin-18-mediated neutrophil infiltration and lung inflammation following burn injury in rats Am J Physiol Lung Cell Mol Physiol, May 1, 2007; 292(5): L1193 - L1201. [Abstract] [Full Text] [PDF]

				Y.-C. Hsieh, H.-P. Yu, M. Frink, T. Suzuki, M. A. Choudhry, M. G. Schwacha, and I. H. Chaudry G Protein-Coupled Receptor 30-Dependent Protein Kinase A Pathway Is Critical in Nongenomic Effects of Estrogen in Attenuating Liver Injury after Trauma-Hemorrhage Am. J. Pathol., April 1, 2007; 170(4): 1210 - 1218. [Abstract] [Full Text] [PDF]