Abstract

Mechanisms that regulate inflammation and repair after acute lung injury are incompletely understood. The extracellular matrix glycosaminoglycan hyaluronan is produced after tissue injury and impaired clearance results in unremitting inflammation. Here we report that hyaluronan degradation products require MyD88 and both Toll-like receptor (TLR)4 and TLR2 in vitro and in vivo to initiate inflammatory responses in acute lung injury. Hyaluronan fragments isolated from serum of individuals with acute lung injury stimulated macrophage chemokine production in a TLR4- and TLR2-dependent manner. Myd88(-/-) and Tlr4(-/-)Tlr2(-/-) mice showed impaired transepithelial migration of inflammatory cells but decreased survival and enhanced epithelial cell apoptosis after lung injury. Lung epithelial cell-specific overexpression of high-molecular-mass hyaluronan was protective against acute lung injury. Furthermore, epithelial cell-surface hyaluronan was protective against apoptosis, in part, through TLR-dependent basal activation of NF-kappaB. Hyaluronan-TLR2 and hyaluronan-TLR4 interactions provide signals that initiate inflammatory responses, maintain epithelial cell integrity and promote recovery from acute lung injury.

Keywords

InflammationTLR4TLR2ChemokineToll-like receptorReceptorCancer researchMedicineExtracellular matrixLungImmunologyApoptosisCell biologyBiologyInnate immune systemInternal medicineBiochemistry

MeSH Terms

AnimalsBronchoalveolar Lavage FluidCellsCulturedChemokinesCytokinesEnzyme-Linked Immunosorbent AssayEpithelial CellsHyaluronic AcidLungLung InjuryMacrophagesPeritonealMiceMiceKnockoutMiceTransgenicMolecular WeightToll-Like Receptor 2Toll-Like Receptor 4Wound Healing

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Publication Info

Year
2005
Type
article
Volume
11
Issue
11
Pages
1173-1179
Citations
1376
Access
Closed

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Cite This

Dianhua Jiang, Jiurong Liang, Juan Fan et al. (2005). Regulation of lung injury and repair by Toll-like receptors and hyaluronan. Nature Medicine , 11 (11) , 1173-1179. https://doi.org/10.1038/nm1315

Identifiers

DOI
10.1038/nm1315
PMID
16244651

Data Quality

Data completeness: 86%