Mechanisms of Cytoprotection in Acute Lung Injury

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): The lung is a major target organ for oxidant injury. Damaging effects of reactive oxygen species (ROS) including superoxide and hydroxyl radicals, and hydrogen peroxide, are generated by the incomplete reduction of oxygen. These toxic ROS can damage cellular constituents such as nucleic acids, proteins, and lipids and play a vital role in both acute and chronic inflammatory diseases of the lung such as adult respiratory distress syndrome (ARDS), pulmonary fibrosis, asthma and emphysema. It is now apparent that the expression of a variety of genes are regulated following oxidant lung injury, and some of these gene products such as the gaseous molecules carbon monoxide (CO), nitric oxide (NO), and the growth factor keratinocyte growth factor (KGF), and the antioxidant enzyme extracellular superoxide dismutase (ECSOD) are cytoprotective against oxidant lung injury. It is a unifying hypothesis of this program project that these various cytoprotective molecules mediate their effector protective functions via distinct and overlapping signal transduction pathways. We will test this hypothesis by addressing these aims: 1) We will examine the mechanism by which CO mediates cytoprotection against hyperoxia, in particular the role of p38 MAPK in mediating CO-induced cytoprotection. 2) We will focus on the mechanism by which KGF-induced activation provides survival signaling in response to oxidant lung injury. 3) We will focus on the anti-apoptotic effects of iNOS derived NO in limiting injury to the pulmonary endothelium of intact mice exposed to 100% oxygen and the mechanism by which NO inhibits LPS-induced apoptosis in cultured mouse lung endothelium (MLEC). 4) We will examine the mechanism by which EC-SOD in the lung defend against oxidant-induced lung injury. These proposed studies will provide novel insight into oxidative and signaling mechanisms that contribute to acute lung injury and point to potential new therapeutic targets.