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Hyaluronan Fragments/CD44 Mediate Oxidative Stress–Induced MUC5B Up-Regulation in Airway Epithelium

¹ Division of Pulmonary and Critical Care Medicine, University of Miami, Miller School of Medicine, Miami, Florida; and ² Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom

Correspondence and requests for reprints should be addressed to S. Marina Casalino-Matsuda, Ph.D., Division of Pulmonary and Critical Care Medicine (R-47), University of Miami, Miller School of Medicine, 1600 NW 10th Ave, RMSB 7072A, Miami, FL 33136. E-mail: mmatsuda{at}med.miami.edu

Mucus hypersecretion with elevated MUC5B mucin production is a pathologic feature in many airway diseases associated with oxidative stress. In the present work, we evaluated MUC5B expression in airways and in primary cultures of normal human bronchial epithelial (NHBE) cells, as well as the mechanisms involved in its regulation. We found that oxidative stress generated by cigarette smoke or reactive oxygen species (ROS) induces MUC5B up-regulation in airway epithelium from smokers and in NHBE cells, respectively. We have previously shown that ROS-induced MUC5AC expression in NHBE cells is dependent on hyaluronan depolymerization and epidermal growth factor receptor (EGFR)/mitogen-activated protein kinase (MAPK) activation. Since hyaluronan fragments can activate MAPK through the hyaluronan receptor CD44, and CD44 heterodimerizes with EGFR, we tested whether ROS and/or hyaluronan fragments induce MUC5B mRNA and protein expression through CD44/EGFR. We found that ROS promotes CD44/EGFR interaction, EGFR/MAPK activation, and MUC5B up-regulation that are prevented by blocking CD44 and/or EGFR. These results were mimicked by hyaluronan fragments. In summary, our results show that oxidative stress in vivo (cigarette smoke) or in vitro (ROS) induces MUC5B up-regulation. This ROS-induced MUC5B expression requires CD44 as well as EGFR and MAPK activation. In addition, we also provide evidence that hyaluronan fragments are sufficient to induce CD44/EGFR interaction and downstream signaling that results in MUC5B up-regulation, suggesting that hyaluronan depolymerization during inflammatory responses could be directly involved in the induction of mucus hypersecretion.

Key Words: MUC5B • hyaluronan fragments • CD44 • airway epithelium

CLINICAL RELEVANCE This study shows that oxidative stress induces MUC5B up-regulation in airway epithelium. In addition, it provides a mechanistic link between oxidative stress–induced hyaluronan depolymerization and increased MUC5B, characteristic of asthma and chronic obstructive pulmonary disease.