High levels of reactive oxygen and nitrogen species (ROS/RNS) and type 2 T helper (TH) lymphocyte production of cytokines, such as IL-4 and IL-13, typify asthmatic airway inflammation. Our studies identify a new mechanistic link by which ROS and antioxidants serve as physiologic regulators of IL-4/IL-13-induced signal transduction and TH2 responses. The protein tyrosine phosphatase (PTP1B) that physically associates with and dephosphorylates the IL-4/IL-13 receptor is inactivated by oxidation, which enables and enhances the TH2 responses of the cell. Further, we show that PTP1B function is restored, and signal transduction turned off, by specific antioxidant peroxiredoxins (Prx). Here, we investigate whether this orderly selective reducing-oxidizing (redox) activation and inactivation of the TH2-cytokine signaling cascade is adulterated under the conditions of excess ROS/RNS and deficient antioxidants that are well-established to exist in the asthmatic airway. In this context, asthmatic airway epithelial cells synthesize high levels of nitric oxide (NO), which reacts with superoxide to form RNS that cause protein tyrosine nitration/inactivation Using proteomic approaches, we identify that antioxidant proteins, which attenuate IL-4/IL-13 signal transduction, are nitrated in the asthmatic airway, i.e. Prx VI, catalase and Mn superoxide dismutase (MnSOD). New preliminary data also suggest that mitochondria contribute to the excess ROS in asthma; mitochondria in human asthmatic airway epithelial cells are pathologic on the basis of dysmorphic appearance, increased numbers, loss of mitochondrial MnSOD activity, low cellular ATP &high lactate levels, and low levels of uncoupling protein-2 (UCP-2), a mitochondrial inner membrane protein that acts as a major negative regulator of ROS production. Altogether these data support the concept that TH2 pathways may be more easily activated, robust and longer-lasting in the ROS/RNS-rich, antioxidant-deficient environment of the asthmatic airway. Accordingly, Project 1 tests the hypothesis that high levels of ROS/RNS and depletion of antioxidants are fundamental determinants of the magnitude and duration of IL 4/IL-13-mediated airway epithelial cell signaling and subsequent TH2 responses that drive asthmatic inflammation. In step with the TPPG goals, we propose mechanistic aims to uncover knowledge that will translate into innovative care for asthma, e.g. redox-sensitive radionuclide imaging and metabolic diets to reduce mitochondrial ROS production. Project 1 draws on the strong complementary skills, unique expertise and resources in the TPPG's tightly synergistic group, and depends heavily upon the shared clinical samples and murine models provided by Cores.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Program Projects (P01)
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Special Emphasis Panel (ZHL1-CSR-A)
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Cleveland Clinic Lerner
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