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 partially 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 angiogenesis and 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. Finally, we investigated the effect of a inter-alpha heavy chain, called ITIH4, in inflammation. We have hitherto established that ITIH4 inhibits cell migration, but appears to promote cell activation after endtoxin lung injury. In a model of infectious lung injury, ITIH4 promotes bacterial clearance and thus inhibits lung injury. Thus, ITIH4 plays an important role in the lung response to environmental (infectious and non-infectious) injury.

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Hilton, Gina M; Taylor, Alexia J; Hussain, Salik et al. (2017) Mapping differential cellular protein response of mouse alveolar epithelial cells to multi-walled carbon nanotubes as a function of atomic layer deposition coating. Nanotoxicology 11:313-326
Hussain, Salik; Ji, Zhaoxia; Taylor, Alexia J et al. (2016) Multiwalled Carbon Nanotube Functionalization with High Molecular Weight Hyaluronan Significantly Reduces Pulmonary Injury. ACS Nano 10:7675-88
Garantziotis, Stavros; Brezina, Martin; Castelnuovo, Paolo et al. (2016) The role of hyaluronan in the pathobiology and treatment of respiratory disease. Am J Physiol Lung Cell Mol Physiol 310:L785-95
Hussain, Salik; Kodavanti, Preeti P; Marshburn, Jamie D et al. (2016) Decreased Uptake and Enhanced Mitochondrial Protection Underlie Reduced Toxicity of Nanoceria in Human Monocyte-Derived Macrophages. J Biomed Nanotechnol 12:2139-2150
Lamas, Adelaida; Marshburn, Jamie; Stober, Vandy P et al. (2016) Effects of inhaled high-molecular weight hyaluronan in inflammatory airway disease. Respir Res 17:123
Miller, Aubrey; Yeskey, Kevin; Garantziotis, Stavros et al. (2016) Integrating Health Research into Disaster Response: The New NIH Disaster Research Response Program. Int J Environ Res Public Health 13:
Dagnino, Sonia; Strynar, Mark J; McMahen, Rebecca L et al. (2016) Identification of Biomarkers of Exposure to FTOHs and PAPs in Humans Using a Targeted and Nontargeted Analysis Approach. Environ Sci Technol 50:10216-25
Jewell, Christine M; Katen, Kevin S; Barber, Lisa M et al. (2016) Healthy Glucocorticoid Receptor N363S Carriers Dysregulate Gene Expression Associated with Metabolic Syndrome. Am J Physiol Endocrinol Metab :ajpendo.00105.2016
Lauer, Mark E; Dweik, Raed A; Garantziotis, Stavros et al. (2015) The Rise and Fall of Hyaluronan in Respiratory Diseases. Int J Cell Biol 2015:712507
Cyphert, Jaime M; Trempus, Carol S; Garantziotis, Stavros (2015) Size Matters: Molecular Weight Specificity of Hyaluronan Effects in Cell Biology. Int J Cell Biol 2015:563818

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