Matrix regulation of lung injury, inflammation, and repair: the role of innate immunity

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.

Figure 1.

CD44 deficiency leads to increased mortality after bleomycin-induced lung injury. Reproduced by permission from Reference . Copyright © 2002 The American Association for the Advancement of Science.

Figure 2.

CD44 deficiency leads to unremitting lung inflammation after bleomycin-induced lung injury.

Figure 3.

CD44 deficiency leads to impaired clearance of hyaluronan after bleomycin-induced lung injury. Reproduced by permission from Reference . Copyright © 2002 The American Association for the Advancement of Science.

Figure 4.

Hyaluronan (HA) fragments stimulate chemokine expression through MyD88. Cxcl2 mRNA expression by peritoneal macrophages from wild-type (wt) or Myd88^−/− mice treated with HA fragments detected by Northern analysis. Reproduced by permission from Reference .

Figure 5.

HA fragments stimulate chemokine expression through both Toll-like receptor 4 (TLR4) and TLR2. Macrophage inflammatory protein (MIP)-1β mRNA expression by peritoneal macrophages from wt, TLR2^−/−, TLR4^−/−, or TLR2^−/−/TLR4^−/− mice treated with HA fragments or LPS in the presence or absence (underlined) of polymyxin B, detected by Northern analysis. Reproduced by permission from Reference .

Figure 6.

TLRs and HA regulate lung cell apoptosis. TUNEL staining of apoptosis from lung tissue sections of wild-type, Myd88^−/−, and Tlr2^−/−/Tlr4^−/− mice 5 d after bleomycin injury. Aw = airway; Ep = airway epithelial cells; En = endothelial cells. Reproduced by permission from Reference .