Regulation of lung injury and repair by Toll-like receptors and hyaluronan

Jiang, D. et al. Nature Medicine 11, 1173 – 1179, 2005

 Speaker: 葉恭誌                     Date: 2006/06/07 13:00~14:00

Commentator: 王崇任醫師             Place: 601教室

Abstract:

Acute lung injury is a major cause of acute respiratory failure with high morbidity and mortality in critically ill patients. However, mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix hyaluronan is degraded and accumulated after tissue injury and impaired clearance results in unremitting inflammation (1). Recent studies have showed that hyaluronan oligomers can signal through TLR4 in dendritic cells (2). In this report, the authors want to investigate the interactions between hyaluronan and TLRs in noninfectious lung injury. They found that the effect of hyaluronan fragments on chemokine production in macrophage was impaired in MyD88 knockout and TLR2/TLR4 double-knockout mice. Furthermore, they examined the role of MyD88, TLR2 and TLR4 in mice treated with bleomycin, a noninfectious model of lung injury. Surprisingly, a marked increase in lung jury in the knockout mice, as measured by increases in interstitial thickness in lung and, protein accumulation in bronchoalveolar lavage fluid, although they were less inflammatory cells infiltration. They also found that bleomycin-treated TLR2/TLR4 knockout mice appeared to involve excess cell apoptosis. Moreover, mice treated with Pep-1, a peptide that block hyaluronan binding, had enhanced apoptotic injury in response to bleomycin, as also seen in TLR2/TLR4 knockout mice. Selective overexpression of high-molecular-mass hyaluronan in lung protected mice from apoptosis, in part, through TLR-dependent basal activation of NF-kB. Taken together, depending on the form of hyaluronan signaling through TLR2 and TLR4, either lung inflammation or tissue protection will result. Soluble degradation fragments of hyaluronan, produced as a result of injury, will cause inflammation. Endogenous high-molecular-mass hyaluronan will prevent apoptosis of epithelial cells, thereby preventing lung injury during inflammation and ultimately promoting repair.

References:

1.      Teder, P. et al. Resolution of lung inflammation by CD44. Science 296, 155-158, 2004.

2.      Termeer, C. et al. Oligosaccharides of hyaluronan activate dendritic cells via toll-like receptor 4. J. Exp. Med. 195, 99-111, 2002.