High levels of reacfive oxygen and nitrogen species (ROS/RNS) and type 2 T helper (TH) lymphocyte production of cytokines, such as IL-4 and IL-13, typify asthmafic airway inflammation. Our studies identify a new mechanistic link by which ROS and anfioxidants serve as physiologic regulators of IL-4/IL-13-induced signal transducfion and TH2 responses. The protein tyrosine phosphatase (PTP1B) that physically associates with and dephosphorylates the IL-4/IL-13 receptor is inacfivated by oxidafion, which enables and enhances the TH2 responses of the cell. Further, we show that PTP1B funcfion is restored, and signal transducfion turned off, by specific anfioxidant peroxiredoxins (Prx). Here, we investigate whether this orderly selecfive reducing-oxidizing (redox) activation and inacfivafion of the TH2-cytokine signaling cascade is adulterated under the conditions of excess ROS/RNS and deficient anfioxidants that are well-established to exist in the asthmafic airway. In this context, asthmafic airway epithelial cells synthesize high levels of nitric oxide (NO), which reacts with superoxide to form RNS that cause protein tyrosine nitrafion/inactivafion Using proteomic approaches, we identify that anfioxidant proteins, which attenuate IL-4/IL-13 signal transducfion, are nitrated in the asthmatic ainway, 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 asthmafic ainway 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 producfion. Altogether these data support the concept that TH2 pathways may be more easily activated, robust and longer-lasfing in the ROS/RNS-rich, anfioxidant-deficient environment of the asthmatic ainway. Accordingly, Project 1 tests the hypothesis that high levels of ROS/RNS and deplefion of anfioxidants are fundamental determinants of the magnitude and durafion of IL 4/IL-13-mediated ainway epithelial cell signaling and subsequent TH2 responses that drive asthmafic inflammafion. In step with the TPPG goals, we propose mechanisfic 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 producfion. Project 1 draws on the strong complementary skills, unique expertise and resources in the TPPG's fightly 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)
Project #
Application #
Study Section
Special Emphasis Panel (ZHL1-CSR-A (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Cleveland Clinic Lerner
United States
Zip Code
Herjan, Tomasz; Hong, Lingzi; Bubenik, Jodi et al. (2018) IL-17-receptor-associated adaptor Act1 directly stabilizes mRNAs to mediate IL-17 inflammatory signaling. Nat Immunol 19:354-365
Sweeny, Elizabeth A; Singh, Anuradha Bharara; Chakravarti, Ritu et al. (2018) Glyceraldehyde-3-phosphate dehydrogenase is a chaperone that allocates labile heme in cells. J Biol Chem 293:14557-14568
Reichard, Andrew; Wanner, Nicholas; Stuehr, Eric et al. (2018) Quantification of airway fibrosis in asthma by flow cytometry. Cytometry A 93:952-958
Asosingh, Kewal; Weiss, Kelly; Queisser, Kimberly et al. (2018) Endothelial cells in the innate response to allergens and initiation of atopic asthma. J Clin Invest 128:3116-3128
Reichard, Andrew; Asosingh, Kewal (2018) The role of mitochondria in angiogenesis. Mol Biol Rep :
Yang, Hui; Zhu, Yun; Chen, Xing et al. (2018) Structure of a prokaryotic SEFIR domain reveals two novel SEFIR-SEFIR interaction modes. J Struct Biol 203:81-89
Cai, Gang; Zhu, Liang; Chen, Xing et al. (2018) TRAF4 binds to the juxtamembrane region of EGFR directly and promotes kinase activation. Proc Natl Acad Sci U S A 115:11531-11536
Zein, Joe G; Love, Thomas E; Erzurum, Serpil C (2017) Asthma Is Associated with a Lower Risk of Sepsis and Sepsis-related Mortality. Am J Respir Crit Care Med 196:787-790
Zepp, Jarod A; Zhao, Junjie; Liu, Caini et al. (2017) IL-17A-Induced PLET1 Expression Contributes to Tissue Repair and Colon Tumorigenesis. J Immunol 199:3849-3857
Stober, Vandy P; Johnson, Collin G; Majors, Alana et al. (2017) TNF-stimulated gene 6 promotes formation of hyaluronan-inter-?-inhibitor heavy chain complexes necessary for ozone-induced airway hyperresponsiveness. J Biol Chem 292:20845-20858

Showing the most recent 10 out of 136 publications