Complex regulation of pulmonary inflammation and fibrosis by CCL18.
Elevated pulmonary levels of CCL18 have been associated with influx of T lymphocytes, collagen accumulation, and a decline in lung function in pulmonary fibrosis patients. We previously reported that overexpression of CCL18 in mouse lungs triggers selective infiltration of T lymphocytes and moderate lymphocyte-dependent collagen accumulation. We hypothesized that in combination with bleomycin injury, overexpression of CCL18 will worsen the severity of lung inflammation and fibrosis. Mice were infected with a replication-deficient adenovirus encoding CCL18 and then instilled with bleomycin; control mice were challenged with either CCL18 overexpression or bleomycin. Additive effects of CCL18 overexpression and bleomycin injury were observed on pulmonary inflammation, particularly on T-cell infiltration, and increased levels of tumor necrosis factor-alpha, interferon-gamma, matrix metalloproteinase (MMP)-2, and MMP-9. Despite the additive effect on inflammation, CCL18 overexpression unexpectedly attenuated the bleomycin-induced collagen accumulation. Pulmonary levels of active transforming growth factor-beta1 mirrored the changes in collagen levels. Depletion of T cells with antilymphocyte serum or pharmacological inhibition of MMPs with GM6001 abrogated accumulation of collagen and increases in the levels of tumor necrosis factor-alpha, interferon-gamma, and active transforming growth factor-beta1. Thus, CCL18-stimulated T-lymphocytic infiltration is by itself mildly profibrotic to a healthy lung, whereas it partially protects against lung fibrosis in an inflammatory profibrotic pulmonary milieu.
Pochetuhen
Kerill
K
Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland 21201, USA.
Luzina
Irina G
IG
Lockatell
Virginia
V
Choi
Jung
J
Todd
Nevins W
NW
Atamas
Sergei P
SP
D000256:Adenoviridae / Q000235:genetics; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015703:Antigens, CD / Q000032:analysis; D001761:Bleomycin / Q000494:pharmacology; D002478:Cells, Cultured; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology; D003094:Collagen / Q000378:metabolism; D004151:Dipeptides / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D006909:Hydroxyproline / Q000378:metabolism; D007371:Interferon-gamma / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D061965:Matrix Metalloproteinase Inhibitors; D051379:Mice; D008810:Mice, Inbred C57BL; D011014:Pneumonia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000473:pathology; D014162:Transfection / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D000903:Antibiotics, Antineoplastic; D015703:Antigens, CD; D019742:Chemokines, CC; D004151:Dipeptides; D061965:Matrix Metalloproteinase Inhibitors; C078131:N-(2(R)-2-(hydroxamidocarbonylmethyl)-4-methylpentanoyl)-L-tryptophan methylamide; D014409:Tumor Necrosis Factor-alpha; D001761:Bleomycin; D007371:Interferon-gamma; D003094:Collagen; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D006909:Hydroxyproline