Regulation of lung injury and repair by Toll-like receptors and hyaluronan.
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.
Jiang
Dianhua
D
Department of Medicine, Section of Pulmonary and Critical Care Medicine, Yale University School of Medicine, 333 Cedar Street, New Haven, Connecticut 06520, USA.
Liang
Jiurong
J
Fan
Juan
J
Yu
Shuang
S
Chen
Suping
S
Luo
Yi
Y
Prestwich
Glenn D
GD
Mascarenhas
Marcella M
MM
Garg
Hari G
HG
Quinn
Deborah A
DA
Homer
Robert J
RJ
Goldstein
Daniel R
DR
Bucala
Richard
R
Lee
Patty J
PJ
Medzhitov
Ruslan
R
Noble
Paul W
PW
D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002478:Cells, Cultured; D018925:Chemokines / Q000032:analysis; D016207:Cytokines / Q000032:analysis; D004797:Enzyme-Linked Immunosorbent Assay; D004847:Epithelial Cells / Q000187:drug effects; D006820:Hyaluronic Acid / Q000737:chemistry / Q000378:metabolism* / Q000494:pharmacology; D008168:Lung / Q000503:physiopathology; D055370:Lung Injury; D017737:Macrophages, Peritoneal / Q000187:drug effects; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D008970:Molecular Weight; D051195:Toll-Like Receptor 2 / Q000235:genetics / Q000502:physiology*; D051197:Toll-Like Receptor 4 / Q000235:genetics / Q000502:physiology*; D014945:Wound Healing
D018925:Chemokines; D016207:Cytokines; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D006820:Hyaluronic Acid