Mechanism of Impaired Local Hyaluronan Turnover in Bleomycin-induced Lung Injury in Rat

Abstract

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.

Mesenchymal stem cell engraftment in lung is enhanced in response to bleomycin exposure and ameliorates its fibrotic effects

“…The homing and engraftment of MSCs in lung may have been augmented by engagement of their CD44 receptor by HA and osteopontin. BLM exposure is known to increase expression of HA in lung (16,17), and we have shown in this report that osteopontin mRNA levels are also increased under these conditions. Alternatively, release of cytokines and mitogens by immune-infiltrating cells may also affect the homing, engraftment, and proliferative status of MSCs in lung.…”

“…Interaction between CD44 and HA is fundamental for the normal development of the lung and the repair of lung injury (15). Although BLM exposure is known to induce expression of HA in lung (16,17), its effect on osteopontin expression is not well characterized. Accordingly, we evaluated the effects of BLM exposure on expression levels of osteopontin mRNA in the lungs of BLM-sensitive strains (C57BL͞6 and 129͞J).…”

Pulmonary fibrosis: patterns and perpetrators

“…The development of this fibrosis was dependent on the hyaluronan receptor CD44 (95). Hyaluronan is a glycosaminoglycan produced in great abundance during noninfectious lung injury and regulates the inflammatory response (95,96). Mice with deletion of HAS2 in mesenchymal cells fail to develop the same degree of fibrosis as wild-type mice (95).…”

Role of hyaluronan and hyaluronan-binding proteins in lung pathobiology

“…A prevalent animal model for noninfectious lung injury is intratracheal administration of bleomycin, which causes an acute pulmonary epithelial cell injury and an inflammatory response that later subsides and develops into lung fibrosis (83). Lung CD44 expression is increased in the initial inflammatory response, along with a transient increase in HA concentration in the lung interstitium (138). In the CD44 knockout mouse, the bleomycin-induced acute inflammatory response persists, leading to excess immune cell recruitment to the lungs, excess inflammatory cytokine production, decreased transforming growth factor-␤ activation, progressive HA fragment (Ͻ5 ϫ 10 5 M r ) accumulation, and, ultimately, death (139).…”