Environmental tissue injury affects extracellular matrix (ECM) both directly and indirectly: environmental stimuli may directly modify the composition of matrix, e.g. inhaled ozone exposure leads to breakdown of high molecular weight hyaluronan (an abundant ECM component) to low-molecular weight fragments; indirectly, environmental injury induces de-novo production of ECM components or translocation of ECM molecules into the interstitial space, e.g. the serum protein inter-alpha-trypsin inhibitor (IaI) extravasates to the interstitium in fibrotic lung injury. Our research focuses on these two abundant yet understudied molecules, and evaluates how they affect the response to tissue injury. Concretely, our research touches on 2 separate but inter-related subjects: 1) To investigate the role of IaI and hyaluronan in airway hyperreactivity after environmental exposures; 2) To investigate the role of IaI and hyaluronan in tissue healing after injury In the first Aim, we were able to show that low-molecular weight hyaluronan is released in the lung airways after ozone exposure in the murine model. Furthermore, we showed that hyaluronan binding through IaI and the cell receptor CD44 is necessary for the mediation of airway hyperreactivity. CD44 is acting in co-receptor fashion with the innate immune receptor TLR4. Finally, hyaluronan binding blockade, IaI blockade, or high molecular weight hyaluronan can be used therapeutically to ameliorate airway hyperreactivity in the mouse model. We have identified a number of agents that can effectively inhibit airway hyperresponsiveness in various mouse models of asthma. Two patent applications are pending and expansion into clinical studies is actively pursued. In the second Aim, we investigate the role of IaI and hyaluronan in lung injury. We have showed that IaI and hyaluronan are necessary for angiogenesis after lung injury in the mouse model, and that IaI and hyaluronan colocalize in the fibrotic areas of human patients with pulmonary fibrosis, particularly around areas of neovascularization. Furthermore, we showed that IaI serum levels in pulmonary fibrosis patients are higher than in control subjects and correlate inversely with gas exchange capacity in these subjects. Furthermore we identified novel IaI interactions, namely with the ECM molecules complement C3, C4, vitronectin and tenascin C. These interactions appear to protect against lung inflammation as well as support epithelial wound healing. Other interacting agents have been also identified. IaI therefore emerges as a multipotent tissue-healing factor with potential therapeutic applications.

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8
Fiscal Year
2015
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Name
U.S. National Inst of Environ Hlth Scis
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Tighe, Robert M; Garantziotis, Stavros (2018) Hyaluronan interactions with innate immunity in lung biology. Matrix Biol :
Sivakumar, Aravind; Mahadevan, Aparna; Lauer, Mark E et al. (2018) Midgut Laterality Is Driven by Hyaluronan on the Right. Dev Cell 46:533-551.e5
Stober, Vandy P; Garantziotis, Stavros (2018) Assessment of Ozone-Induced Lung Injury in Mice. Methods Mol Biol 1809:301-314
Zhou, Ting; Yu, Zhihong; Jian, Ming-Yuan et al. (2018) Instillation of hyaluronan reverses acid instillation injury to the mammalian blood gas barrier. Am J Physiol Lung Cell Mol Physiol 314:L808-L821
Goulding, David R; Nikolova, Viktoriya D; Mishra, Lopa et al. (2018) Inter-?-inhibitor deficiency in the mouse is associated with alterations in anxiety-like behavior, exploration and social approach. Genes Brain Behav :e12505
Ni, Kevin; Gill, Amar; Tseng, Victor et al. (2018) Rapid clearance of heavy chain-modified hyaluronan during resolving acute lung injury. Respir Res 19:107
Garantziotis, Stavros; Tighe, Robert M (2018) Inflammation Gets on the Lung's Nerves: IL-17 and Neuroendocrine Cells Mediate Ozone Responses in Obesity. Am J Respir Cell Mol Biol 58:284-285
Schurman, Shepherd H; Bravo, Mercedes A; Innes, Cynthia L et al. (2018) Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity. Sci Rep 8:12713
Walker, Julia K L; Theriot, Barbara S; Ghio, Michael et al. (2017) Targeted HAS2 Expression Lessens Airway Responsiveness in Chronic Murine Allergic Airway Disease. Am J Respir Cell Mol Biol 57:702-710
Trempus, Carol S; Song, Weifeng; Lazrak, Ahmed et al. (2017) A novel role for primary cilia in airway remodeling. Am J Physiol Lung Cell Mol Physiol 313:L328-L338

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