The work, as detailed in this proposal, has focused on the mechanism(s) of protection that IL-11 and IL-6 confers in the setting of hyperoxic lung injury. We compared the susceptibility to 100% oxygen of transgenic mice in which IL-11 or IL-6 is overexpressed in an airway-specific fashion and transgene (-) littermates. These studies demonstrated that both IL-11 and IL-6 significantly ameliorates hyperoxia-induced injury. Transgene (+) animals live significantly longer in 100% oxygen and this protective effect is associated with diminished ultrastructural evidence of endothelial injury, alveolar protein leak and lipid peroxidation, while alterations in antioxidants are not of a magnitude to explain this effect. The protective effects of these cytokines are associated with a significant decrease in hyperoxia-induced cell death and DNA fragmentation and the enhanced expression of the Bcl-2 proteins. These studies lead us to hypothesize that IL-11 and IL-6 are protective in the setting of hyperoxic lung injury and this protection is mediated, in part by the inhibition of cell death pathways. To test this hypothesis, we propose to:
Aim 1 : Characterize the signal transduction pathways that mediate IL-11 and IL-6 induced protection from oxidant stress in vitro and examine the relationship to upregulation of mediators of cell death. We will characterize the contributions of the known components of the IL-11 and IL-6 receptors (IL-11Ra, IL-6R, and gp 130) as well as four different but interacting signaling pathways (JAK/STAT; ras/ERK; rac/JNK, and p38) to the induction of protective effects on cultured human pulmonary epithelial and microvascular endothelial cells incubated in the presence and absence of oxidant stress.
Aim 2 : Evaluate the contribution(s) of Bcl 2 family proteins to protection of pulmonary epithelial and microvascular endothelial cells in vitro. We will characterize the effects of Bcl 2 family proteins (Bcl-2, Bcl-x, and Bax) by taking advantage of our ability to: (a) transfect and overexpress many of these moieties in primary human cells; (b) use anti-sense approaches to prevent the induction of potential apoptosis regulators in human pulmonary epithelial and microvascular endothelial cells incubated in the presence and absence of oxidant stress; (c) transfect and overexpress many of these moieties in vivo.
Aim 3 : Evaluate the contribution(s) of Bcl 2 family proteins to protection in vivo. Our studies and those in the literature suggest that the protective effects of IL-6 type cytokines are mediated, at least in part, by their ability to augment the production of specific Bcl-2 family members. We will test this hypothesis by characterizing the effects of IL-11 and IL-6 on the levels of these proteins and the mRNA that encode them and generating and characterizing the sensitivity to 100% O2 of mice that overexpress these moieties.
|Kolliputi, Narasaiah; Shaik, Rahamthulla S; Waxman, Aaron B (2010) The inflammasome mediates hyperoxia-induced alveolar cell permeability. J Immunol 184:5819-26|
|Kolliputi, Narasaiah; Waxman, Aaron B (2009) IL-6 cytoprotection in hyperoxic acute lung injury occurs via suppressor of cytokine signaling-1-induced apoptosis signal-regulating kinase-1 degradation. Am J Respir Cell Mol Biol 40:314-24|
|Steiner, M Kathryn; Syrkina, Olga L; Kolliputi, Narasaish et al. (2009) Interleukin-6 overexpression induces pulmonary hypertension. Circ Res 104:236-44, 28p following 244|
|Kolliputi, Narasaiah; Waxman, Aaron B (2009) IL-6 cytoprotection in hyperoxic acute lung injury occurs via PI3K/Akt-mediated Bax phosphorylation. Am J Physiol Lung Cell Mol Physiol 297:L6-16|
|Waxman, Aaron B; Kolliputi, Narasaiah (2009) IL-6 protects against hyperoxia-induced mitochondrial damage via Bcl-2-induced Bak interactions with mitofusins. Am J Respir Cell Mol Biol 41:385-96|
|Lee, Po-Shun; Patel, Sanjay R; Christiani, David C et al. (2008) Plasma gelsolin depletion and circulating actin in sepsis: a pilot study. PLoS One 3:e3712|
|Tolle, James; Waxman, Aaron; Systrom, David (2008) Impaired systemic oxygen extraction at maximum exercise in pulmonary hypertension. Med Sci Sports Exerc 40:3-8|
|Chetty, Anne; Cao, Gong-Jie; Severgnini, Mariano et al. (2008) Role of matrix metalloprotease-9 in hyperoxic injury in developing lung. Am J Physiol Lung Cell Mol Physiol 295:L584-92|
|Chetty, Anne; Cao, Gong-Jee; Manzo, Nicholas et al. (2008) The role of IL-6 and IL-11 in hyperoxic injury in developing lung. Pediatr Pulmonol 43:297-304|
|Barker, George F; Manzo, Nicholas D; Cotich, Kara L et al. (2006) DNA damage induced by hyperoxia: quantitation and correlation with lung injury. Am J Respir Cell Mol Biol 35:277-88|
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