The Role of Hyaluronan And Inter-Alpha-Trypsin Inhibitor in Tissue Injury

National Institute Of Environmental Health Sciences

Investigators

Linked publications, trials & patents

Abstract

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 lung injury 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 several types of lung injury and mediates inflammation and tissue injury. Hyaluronan binding 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. A patent application was granted recently. Two clinical studies have been completed and have shown that inhaled high molecular weight hyaluronan is effective as treatment in acute COPD exacerbation and viral pneumonia. In the second Aim, we investigate the role of IaI and hyaluronan in tissue healing. 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. We are currently conducting a clinical trial with a hyaluronan synthesis inhibitor, 4-methylumbelliferone, to evaluate utility in pulmonary fibrosis treatment.