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Mechanisms of ODN-Induced Epithelial Reactive Oxygen Species Generation and Its Role in Inducible Resistance to Influenza Infection
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A5495 - Mechanisms of ODN-Induced Epithelial Reactive Oxygen Species Generation and Its Role in Inducible Resistance to Influenza Infection
Author Block: Y. Wang1, V. Kulkarni2, M. Leiva-Juarez3, S. Wali4, F. Gulraiz1, M. Chavez Cavazos1, S. E. Evans5; 1Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, United States, 2Pulmonary medicine, Houston, TX, United States, 3UT MD Anderson Cancer Center, Houston, TX, United States, 4Pulmonary Medicine, Houston, TX, United States, 5Pulmonary Medicine, University of Texas MD Anderson Cancer Ctr, Houston, TX, United States.
The lung epithelium constitutes the first line of defense against microbial infection in lung. By stimulating the lung epithelium with a synergistic inhaled treatment consisting of TLR2/6 and TLR9 agonists (Pam2-ODN), mice are robustly protected against Pseudomonas and influenza pneumonia. We reported that isolated lung epithelial cells could be stimulated to generate robust antiviral responses that reduce viral burden and that the protection required induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase (DUOX) sources. We recently identified that ODN is the primary stimulator of mitochondrial and DUOX ROS generation. To study the mechanisms of ODN-induced mitochondria ROS (mitoROS) formation, we treated human lung epithelial cells with mitochondria electron transport chain complex inhibitors and found that combination treatment with TTFA and FCCP significantly decreased Pam2-ODN induced mitoROS generation, while rotenone, antimycin A, sodium azide and oligomycin did not. We hypothesize that reverse electron transfer by mitochondria complex I contributes to ODN-induced mitoROS generation. Since superoxide is the sole ROS species generated by the mitochondria electron transport machinery, we hypothesize that mitoROS acts as a second messenger to activate downstream antiviral events. We are currently investigating both hypotheses using tissue culture and transgenic mouse as models. The findings in this study have the potential to offer insights for rational development of alternate strategies to protect against fatal lung infections in patients with impaired immunity.
Author Block: Y. Wang1, V. Kulkarni2, M. Leiva-Juarez3, S. Wali4, F. Gulraiz1, M. Chavez Cavazos1, S. E. Evans5; 1Pulmonary Medicine, UT MD Anderson Cancer Center, Houston, TX, United States, 2Pulmonary medicine, Houston, TX, United States, 3UT MD Anderson Cancer Center, Houston, TX, United States, 4Pulmonary Medicine, Houston, TX, United States, 5Pulmonary Medicine, University of Texas MD Anderson Cancer Ctr, Houston, TX, United States.
The lung epithelium constitutes the first line of defense against microbial infection in lung. By stimulating the lung epithelium with a synergistic inhaled treatment consisting of TLR2/6 and TLR9 agonists (Pam2-ODN), mice are robustly protected against Pseudomonas and influenza pneumonia. We reported that isolated lung epithelial cells could be stimulated to generate robust antiviral responses that reduce viral burden and that the protection required induction of epithelial reactive oxygen species (ROS) from both mitochondrial and dual oxidase (DUOX) sources. We recently identified that ODN is the primary stimulator of mitochondrial and DUOX ROS generation. To study the mechanisms of ODN-induced mitochondria ROS (mitoROS) formation, we treated human lung epithelial cells with mitochondria electron transport chain complex inhibitors and found that combination treatment with TTFA and FCCP significantly decreased Pam2-ODN induced mitoROS generation, while rotenone, antimycin A, sodium azide and oligomycin did not. We hypothesize that reverse electron transfer by mitochondria complex I contributes to ODN-induced mitoROS generation. Since superoxide is the sole ROS species generated by the mitochondria electron transport machinery, we hypothesize that mitoROS acts as a second messenger to activate downstream antiviral events. We are currently investigating both hypotheses using tissue culture and transgenic mouse as models. The findings in this study have the potential to offer insights for rational development of alternate strategies to protect against fatal lung infections in patients with impaired immunity.
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