Hyaluronan Mediates Ozone-induced Airway Hyperresponsiveness in Mice

Stavros Garantziotis,Zhuowei Li,Erin N Potts,Koji Kimata,Lisheng Zhuo,Daniel L Morgan,Rashmin C Savani,Paul W Noble,W Michael Foster,David A Schwartz,John W Hollingsworth

doi:10.1074/jbc.m802400200

Abstract

Ozone is a common urban environmental air pollutant and significantly contributes to hospitalizations for respiratory illness. The mechanisms, which regulate ozone-induced bronchoconstriction, remain poorly understood. Hyaluronan was recently shown to play a central role in the response to noninfectious lung injury. Therefore, we hypothesized that hyaluronan contributes to airway hyperreactivity (AHR) after exposure to ambient ozone. Using an established model of ozone-induced airways disease, we characterized the role of hyaluronan in airway hyperresponsiveness. The role of hyaluronan in response to ozone was determined by using therapeutic blockade, genetically modified animals, and direct challenge to hyaluronan. Ozone-exposed mice demonstrate enhanced AHR associated with elevated hyaluronan levels in the lavage fluid. Mice deficient in either CD44 (the major receptor for hyaluronan) or inter-alpha-trypsin inhibitor (molecule that facilitates hyaluronan binding) show similar elevations in hyaluronan but are protected from ozone-induced AHR. Mice pretreated with hyaluronan-binding peptide are protected from the development of ozone-induced AHR. Overexpression of hyaluronan enhances the airway response to ozone. Intratracheal instillation of endotoxin-free low molecular weight hyaluronan induces AHR dependent on CD44, whereas instillation of high molecular weight hyaluronan protects against ozone-induced AHR. In conclusion, we demonstrate that hyaluronan mediates ozone-induced AHR, which is dependent on the fragment size and both CD44 and inter-alpha-trypsin inhibitor. These data support the conclusion that pulmonary matrix can contribute to the development of airway hyperresponsiveness.

Highlights

Ozone is a commonly encountered urban air pollutant that significantly contributes to increased morbidity [1,2,3,4] and can lead to a significant economic burden
Hyaluronan was visible around subepithelial myocytes (Fig. 3), whereas CD44 and hyaluronan colocalized on alveolar macrophages (Fig. 4)
We found that these mice were increased epithelial expression of hyaluronan, we observed a protected from ozone-induced airway hyperresponsiveness, similar degree of lung injury as quantified by lung lavage protein when compared with C57BL/6J mice (Fig. 5A)

Summary

Introduction

Ozone is a commonly encountered urban air pollutant that significantly contributes to increased morbidity [1,2,3,4] and can lead to a significant economic burden. Mice exposed to ozone demonstrate elevated lung lavage fluid levels of hyaluronan, which is of low molecular weight. Pretreatment of mice with hyaluronan-binding peptide or high molecular weight hyaluronan protects animals from the development of ozone-induced AHR.

Results

Conclusion