Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition.
Recent studies support the concept that pulmonary granulomatous inflammation directed by interferon (IFN)-gamma, interleukin (IL)-12, and nitric oxide usually resolves in the absence of fibrosis. To determine whether nitric oxide participates in modulating the fibrotic response during the development of pulmonary granulomas in response to purified protein derivative (PPD), mice presensitized to PPD received daily intraperitoneal injections of N(G)-nitro-D-arginine-methyl ester (D-NAME), N(G)-nitro-L-arginine-methyl ester (L-NAME), or aminoguanidine after delivery of PPD-coated beads to the lungs. Eight days later, morphometric analysis of lung granulomas revealed that L-NAME-treated mice when challenged with PPD in vitro for 36 hours had the largest pulmonary granulomas and the greatest collagen deposition among the treated groups. In addition, equivalent numbers of dispersed lung cells from L-NAME- and aminoguanidine-treated mice produced significantly higher levels of IL-4, monocyte chemoattractant protein (MCP)-1, and macrophage inflammatory protein (MIP)-1alpha and significantly lower levels of eotaxin compared with D-NAME-treated mice. Cultures of dispersed lung cells from L-NAME-treated mice also produced significantly more IL-10 and less IL-12 compared with similar numbers of dispersed lung cells from D-NAME-treated mice. Cultures of isolated lung fibroblasts from L-NAME-treated mice expressed higher levels of C-C chemokine receptor 2 (CCR2) and CCR3 mRNA and contained less MCP-1 and eotaxin protein than a similar number of fibroblasts from D-NAME-treated mice. Thus, nitric oxide appears to regulate the deposition of extracellular matrix in lung granulomas through the modulation of the cytokine and chemokine profile of these lesions. Alterations in the cytokine, chemokine, and procollagen profile of this lesion may be a direct effect of nitric oxide on the pulmonary fibroblast and provide an important signal for regulating fibroblast activity during the evolution of chronic lung disease.
Hogaboam
C M
CM
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. hogaboam@path.med.umich.edu
Gallinat
C S
CS
Bone-Larson
C
C
Chensue
S W
SW
Lukacs
N W
NW
Strieter
R M
RM
Kunkel
S L
SL
D000818:Animals; D002478:Cells, Cultured; D054413:Chemokine CCL11; D018932:Chemokine CCL2 / Q000378:metabolism; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D003094:Collagen / Q000378:metabolism*; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D015769:Granuloma, Respiratory Tract / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D006146:Guanidines / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D008171:Lung Diseases / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D019402:Macrophage Inflammatory Proteins / Q000378:metabolism; D051379:Mice; D008808:Mice, Inbred CBA; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000037:antagonists & inhibitors / Q000502:physiology*; D011347:Procollagen / Q000235:genetics / Q000378:metabolism; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019707:Receptors, Chemokine / Q000378:metabolism; D013047:Specific Pathogen-Free Organisms; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014373:Tuberculin
C515457:Ccl11 protein, mouse; C515335:Ccr2 protein, mouse; C515351:Ccr3 protein, mouse; D054413:Chemokine CCL11; D018932:Chemokine CCL2; D054405:Chemokine CCL3; D054407:Chemokine CCL4; D019742:Chemokines, CC; D016207:Cytokines; D004791:Enzyme Inhibitors; D006146:Guanidines; D007378:Interleukins; D019402:Macrophage Inflammatory Proteins; D011347:Procollagen; D054390:Receptors, CCR2; D054397:Receptors, CCR3; D019707:Receptors, Chemokine; D016212:Transforming Growth Factor beta; D014373:Tuberculin; D009569:Nitric Oxide; D007371:Interferon-gamma; D003094:Collagen; C004479:pimagedine; D019331:NG-Nitroarginine Methyl Ester