Hyaluronan mediates ozone-induced airway hyperresponsiveness in mice.
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.
Garantziotis
Stavros
S
NIEHS, National Institutes of Health, Research Triangle Park, North Carolina 27709, USA.
Li
Zhuowei
Z
Potts
Erin N
EN
Kimata
Koji
K
Zhuo
Lisheng
L
Morgan
Daniel L
DL
Savani
Rashmin C
RC
Noble
Paul W
PW
Foster
W Michael
WM
Schwartz
David A
DA
Hollingsworth
John W
JW
D000510:Alpha-Globulins / Q000494:pharmacology; D000818:Animals; D016535:Bronchial Hyperreactivity / Q000378:metabolism*; D001992:Bronchoalveolar Lavage Fluid; D018960:Hyaluronan Receptors / Q000096:biosynthesis; D006820:Hyaluronic Acid / Q000378:metabolism*; D055370:Lung Injury / Q000473:pathology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008954:Models, Biological; D010126:Ozone; D010455:Peptides / Q000737:chemistry; D014132:Trachea / Q000473:pathology*
D000510:Alpha-Globulins; D018960:Hyaluronan Receptors; D010455:Peptides; C011877:inter-alpha-inhibitor; D010126:Ozone; D006820:Hyaluronic Acid