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PMID: 9846976 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Collagen deposition in a non-fibrotic lung granuloma model after nitric oxide inhibition.

The American journal of pathology ·Vol. 153 ·No. 6 ·1998-12-00 ·Pages 1861-72

Hogaboam CM, Gallinat CS, Bone-Larson C, Chensue SW, Lukacs NW, Strieter RM, Kunkel SL

Abstract

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.

MeSH Terms
Animals Cells, Cultured Chemokine CCL11 Chemokine CCL2/metabolism Chemokine CCL3 Chemokine CCL4 Chemokines, CC Collagen/metabolism Cytokines/metabolism Enzyme Inhibitors/pharmacology Female Fibroblasts/drug effects,metabolism Granuloma, Respiratory Tract/chemically induced,metabolism,pathology Guanidines/pharmacology Interferon-gamma/metabolism Interleukins/metabolism Lung Diseases/chemically induced,metabolism,pathology Macrophage Inflammatory Proteins/metabolism Mice Mice, Inbred CBA NG-Nitroarginine Methyl Ester/pharmacology Nitric Oxide/antagonists & inhibitors,physiology Procollagen/genetics,metabolism Receptors, CCR2 Receptors, CCR3 Receptors, Chemokine/metabolism Specific Pathogen-Free Organisms Transforming Growth Factor beta/metabolism Tuberculin
Chemicals
Ccl11 protein, mouse Ccr2 protein, mouse Ccr3 protein, mouse Chemokine CCL11 Chemokine CCL2 Chemokine CCL3 Chemokine CCL4 Chemokines, CC Cytokines Enzyme Inhibitors Guanidines Interleukins Macrophage Inflammatory Proteins Procollagen Receptors, CCR2 Receptors, CCR3 Receptors, Chemokine Transforming Growth Factor beta Tuberculin Nitric Oxide Interferon-gamma Collagen pimagedine NG-Nitroarginine Methyl Ester
Authors & Affiliations
7 authors, click to expand affiliations / ORCID
Hogaboam C M
Department of Pathology, University of Michigan Medical School, Ann Arbor 48109-0602, USA. hogaboam@path.med.umich.edu
Gallinat C S
Bone-Larson C
Chensue S W
Lukacs N W
Strieter R M
Kunkel S L
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Article Info
Journal
The American journal of pathology
Abbr.
Am J Pathol
ISSN
0002-9440
DOI
10.1016/S0002-9440(10)65700-8
Email
hogaboam@path.med.umich.edu
Published
1998-12-00
Pages
1861-72
Language
English
Region
United States
NLM ID
0370502
PMCID
PMC1866342
Subset
IM
Grants
NIAID NIH HHS · R01 AI036302 · United States
NHLBI NIH HHS · P50 HL056402 · United States
NHLBI NIH HHS · 1P50HL56402 · United States
NHLBI NIH HHS · P01 HL031963 · United States
NHLBI NIH HHS · R37 HL035276 · United States
NHLBI NIH HHS · HL31963 · United States
NIAID NIH HHS · R29 AI036302 · United States
NHLBI NIH HHS · HL35276 · United States
External Links
PubMed source DOI: 10.1016/S0002-9440(10)65700-8 PMC Full Text View journal details
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