Toll-like receptor 4-dependent responses to lung injury in a murine model of pulmonary contusion.
Blunt chest trauma resulting in pulmonary contusion with an accompanying acute inflammatory response is a common but poorly understood injury. We previously demonstrated that toll-like receptor 2 (TLR-2) participates in the inflammatory response to lung injury. We hypothesized that the TLR-4, in an MyD88-dependent manner, may also participate in the response to lung injury. To investigate this, we used a model of pulmonary contusion in the mouse that is similar to that observed clinically in humans and evaluated postinjury lung function, pulmonary neutrophil recruitment, and the systemic innate immune response. Comparisons were made between wild-type mice and mice deficient in TLR-4 or MyD88. We found TLR-4-dependent responses to pulmonary contusion that include hypoxemia, edema, and neutrophil infiltration. Increased expression of IL-6 and chemokine (C-X-C motif) ligand 1 in the bronchoalveolar lavage and serum was also dependent on TLR-4 activation. We further demonstrated that these responses to pulmonary contusion were dependent on MyD88, an adapter protein in the signal transduction pathway mediated by TLRs. These results show that TLRs have a primary role in the response to acute lung injury. Lung inflammation and systemic innate immune responses are dependent on TLR activation by pulmonary contusion.
Hoth
J Jason
JJ
Department of General Surgery, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. jhoth@wfubmc.edu
Wells
Jonathan D
JD
Brownlee
Noel A
NA
Hiltbold
Elizabeth M
EM
Meredith
J Wayne
JW
McCall
Charles E
CE
Yoza
Barbara K
BK
D000818:Animals; D054360:Chemokine CXCL1 / Q000097:blood; D003288:Contusions / Q000503:physiopathology*; D004195:Disease Models, Animal; D007150:Immunohistochemistry; D015850:Interleukin-6 / Q000097:blood; D008171:Lung Diseases / Q000209:etiology / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency; D051197:Toll-Like Receptor 4 / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D054360:Chemokine CXCL1; C475895:Cxcl1 protein, mouse; D015850:Interleukin-6; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4