Successful repair after tissue injury and inflammation requires resolution of the inflammatory response and removal of extracellular matrix breakdown products. We have examined whether the cell-surface adhesion molecule and hyaluronan receptor CD44 plays a role in resolving lung inflammation. CD44-deficient mice succumb to unremitting inflammation following noninfectious lung injury, characterized by impaired clearance of apoptotic neutrophils, persistent accumulation of hyaluronan fragments at the site of tissue injury, and impaired activation of transforming growth factor-beta1. This phenotype was partially reversed by reconstitution with CD44+ cells, thus demonstrating a critical role for this receptor in resolving lung inflammation.

CD44 is a major cell-surface receptor for hyaluronic acid (HA), a glycosaminoglycan component of extracellular matrix. HA-CD44 interactions have been implicated in leukocyte extravasation into an inflammatory site. This study examined the role of CD44 in acute inflammatory responses during pneumonias induced by Escherichia coli and Streptococcus pneumoniae using CD44-deficient mice. In E. coli-induced pneumonia, neutrophil accumulation in the lungs and edema formation was increased by 84% and 88%, respectively, in CD44-deficient mice compared to wild-type mice. In contrast, no difference was observed between these genotypes in S. pneumoniaeinduced pneumonia, and the HA content in the lungs decreased after instillation of S. pneumoniae, but not E. coli, in both genotypes. Studies to determine the mechanisms for this enhanced response showed that: 1) neutrophil apoptosis was not different between these two genotypes in either type of pneumonia; 2) CD44 deficiency resulted in enhanced mRNA expression of several inflammatory genes; and 3) CD44-deficient neutrophils migrated through Matrigel in response to chemoattractants faster and in greater numbers than wild-type neutrophils in vitro and this increase was in part dependent on HA content in the Matrigel. These data demonstrate that CD44 deficiency results in enhanced inflammation in E. coli but not S. pneumoniae-induced pneumonia, suggesting a previously unrecognized role for CD44 in limiting the inflammatory response to E. coli. Neutrophil accumulation at inflammatory sites is an important feature of acute inflammatory responses. During pulmonary inflammation, circulating neutrophils become sequestered within pulmonary capillaries, a process that does not require rolling. Neutrophils then migrate across the endothelium and through the pulmonary interstitium, which contains fibroblasts and extracellular matrix proteins such as collagens and proteoglycans.1-4 Finally, neutrophils migrate between alveolar epithelial cells, often between a type II and a type I pneumocyte, into the airspace. 1,5 CD44 is a type I transmembrane glycoprotein that is expressed by most cell types, including leukocytes, and is the major cell surface receptor for hyaluronan (HA). HA is a nonsulfated glycosaminoglycan component of the extracellular matrix and plays a major role in maintenance of tissue integrity.6 -8 CD44 has 10 different splice variants and neutrophils express the standard CD44 isoform, CD44s.9 CD44 may modulate immunological and inflammatory responses through at least two mechanisms. First, CD44 may play important roles in modulating leukocyte extravasation. Interaction between CD44 and HA is implicated in lymphocyte rolling and extravasation, and optimal binding of these two molecules is modulated by proinflammatory cytokines such as tumor necrosis factor-␣.10 -14 The role of CD44 in mediating neutrophil emigration during acute inflammatory responses is less well understood. Second, CD44 is capable of inducing signal transduction pathways and cell activation. Ligation of C...

Hyaluronan, a linear polysaccharide, is accumulated in lung interstitium during different pathological conditions, causing interstitial edema and thereby impaired lung function. We investigated the mechanism of local hyaluronan turnover during the early phase of bleomycin-induced fibrotic lung injury in rats. The binding of [3H]hyaluronan to alveolar macrophages (AM) established from bleomycin-treated rats 1 and 5 days after induction of injury was decreased 8- and 15-fold, respectively, compared with that of AM from saline-treated control counterparts, but at day 14 returned almost to the normal level. Data was confirmed by quantitative cytochemistry, using fluorescein-labeled hyaluronan. Analysis of the expression of CD44, a receptor for hyaluronan, by Western blotting revealed a 30% increase of CD44 molecules expressed on AM from bleomycin-treated rats at day 5 compared with control rats. In particular a lower molecular mass form of CD44 appeared. No expression of the receptor for hyaluronan-mediated motility (RHAMM) could be detected. The internalization and degradation of [3H]hyaluronan by AM, obtained from bleomycin-treated rats at days 1, 5, and 14, were decreased about 65%, 35%, and 30%, respectively, compared with AM from the control rats. The AM lysosomal hyaluronidase activity did not differ significantly between bleomycin-treated and control rats. Our results indicate that a decreased hyaluronan binding capacity of AM may account for the impairment of internalization and thereby degradation of excessive hyaluronan during the early phase of fibrotic lung injury.