Protection from pulmonary fibrosis in the absence of CCR2 signaling.
Pulmonary fibrosis can be modeled in animals by intratracheal instillation of FITC, which results in acute lung injury, inflammation, and extracellular matrix deposition. We have previously shown that despite chronic inflammation, this model of pulmonary fibrosis is lymphocyte independent. The CC chemokine monocyte-chemoattractant protein-1 is induced following FITC deposition. Therefore, we have investigated the contribution of the main monocyte-chemoattractant protein-1 chemokine receptor, CCR2, to the fibrotic disease process. We demonstrate that CCR2(-/-) mice are protected from fibrosis in both the FITC and bleomycin pulmonary fibrosis models. The protection is specific for the absence of CCR2, as CCR5(-/-) mice are not protected. The protection is not explained by differences in acute lung injury, or the magnitude or composition of inflammatory cells. FITC-treated CCR2(-/-) mice display differential patterns of cellular activation as evidenced by the altered production of cytokines and growth factors following FITC inoculation compared with wild-type controls. CCR2(-/-) mice have increased levels of GM-CSF and reduced levels of TNF-alpha compared with FITC-treated CCR2(+/+) mice. Thus, CCR2 signaling promotes a profibrotic cytokine cascade following FITC administration.
Moore
B B
BB
Division of Pulmonary and Critical Care, Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, MI 48109, USA. Bmoore@umich.edu
Paine
R
R
Christensen
P J
PJ
Moore
T A
TA
Sitterding
S
S
Ngan
R
R
Wilke
C A
CA
Kuziel
W A
WA
Toews
G B
GB
D000818:Animals; D001761:Bleomycin / Q000494:pharmacology; D018932:Chemokine CCL2 / Q000096:biosynthesis; D016207:Cytokines / Q000378:metabolism; D016650:Fluorescein-5-isothiocyanate / Q000494:pharmacology; D051379:Mice; D008817:Mice, Mutant Strains; D011658:Pulmonary Fibrosis / Q000139:chemically induced / Q000209:etiology*; D054390:Receptors, CCR2; D019713:Receptors, CCR5 / Q000172:deficiency / Q000235:genetics; D019707:Receptors, Chemokine / Q000172:deficiency* / Q000235:genetics; D015398:Signal Transduction
C515335:Ccr2 protein, mouse; D018932:Chemokine CCL2; D016207:Cytokines; D054390:Receptors, CCR2; D019713:Receptors, CCR5; D019707:Receptors, Chemokine; D001761:Bleomycin; D016650:Fluorescein-5-isothiocyanate