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Matrix Regulation of Lung Injury, Inflammation, and Repair

The Role of Innate Immunity

Section of Pulmonary and Critical Care Medicine, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut

Correspondence and requests for reprints should be addressed to Paul Noble, M.D., Professor of Medicine, Pulmonary and Critical Care Medicine, Yale University School of Medicine, TAC S441C, PO Box 208057, 333 Cedar Street, New Haven, CT 06520. E-mail: paul.noble{at}yale.edu

ABSTRACT

Mechanisms that regulate host defense after noninfectious tissue injury are incompletely understood. Our laboratory is interested in the role of the extracellular matrix glycosaminoglycan hyaluronan in the regulation of lung inflammation and fibrosis. We have identified key roles for two cell surface receptor systems that interact with hyaluronan to control lung inflammation and tissue repair. Hematopoietic CD44 is necessary to clear hyaluronan fragments that are produced after lung injury. Failure to clear hyaluronan fragments leads to unremitting inflammation. However, in the absence of CD44, alveolar macrophages continue to produce chemokines in response to hyaluronan fragments, implicating another receptor system in controlling macrophage effector function. We found that Toll-like receptors 2 and 4 (TLR2 and TLR4) are responsible for macrophage inflammatory gene expression in response to hyaluronan fragments. Although TLR2 and TLR4 initiate the innate immune response in noninfectious inflammation, they have a protective role against lung injury on alveolar epithelial cells.

Key Words: CD44 • hyaluronan • innate immunity • tissue injury • Toll-like receptors

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