Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators

P. B. Bitterman, M. D. Wewers, S. I. Rennard, S. Adelberg, Ronald Crystal

Research output: Contribution to journalArticle

162 Citations (Scopus)

Abstract

Tissue fibrosis results, in part, from an interaction between growth regulatory molecules released by mononuclear phagocytes and fibroblasts. In the chronic interstitial lung disorders, alveolar macrophages, the mononuclear phagocytes of the lung, are known to spontaneoulsy release two growth factors for fibroblasts, fibronectin and alveolar macrophage-derived growth factor (AMDGF) that together stimulate nonreplicating lung fibroblasts to divide. In addition to these two primary growth promoting signals, alveolar macrophages are able to release other mediators that may have a potential role in modulating lung fibroblast replication in response to these primary signals, including interferon γ (INFγ), prostaglandin E2 (PGE2), and interleukin 1 (IL-1). To evaluate this possibility, we examined the effect of each of these other mediators on lung fibroblast replication in response to fibronectin and AMDGF in serum-free, defined medium. IFNγ had no effect on fibroblast replication. In contrast, PGE2 resulted in a dose-dependent inhibition of fibroblast replication in response to fibronectin and AMDGF with 50% of the maximum inhibition observed at a PGE2 concentration of <10 ng/ml. IL-1, while not active as a primary growth promoting signal, at concentrations of 4-10 U/ml, augmented fibroblast replication in response to fibronectin and AMDGF by 10 to 15%. Temporally, the growth augmenting effect of IL-1 occurred early in the G1 phase of the cell cycle. These data indicate that lung fibroblast replication in response to two of the primary growth promoting signals spontaneoulsy released by alveolar macrophages in the interstitial lung disorders, while uninfluenced by IFNγ, can be inhibited by PGE2 and modestly augmented by IL-1. Understanding the relevant fibroblast growth modulatory signals within the alveolar microenvironment in the chronic interstitial disorders may lead to rational therapeutic strategies designed to interrupt the fibrotic process.

Original languageEnglish
Pages (from-to)700-708
Number of pages9
JournalJournal of Clinical Investigation
Volume77
Issue number3
DOIs
Publication statusPublished - 1 Jan 1986
Externally publishedYes

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Alveolar Macrophages
Fibroblasts
Macrophages
Lung
Interleukin-1
Fibronectins
Dinoprostone
Growth
Phagocytes
Fibroblast Growth Factors
Serum-Free Culture Media
G1 Phase
Interferons
Cell Cycle
Fibrosis
alveolar macrophage growth factor

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators. / Bitterman, P. B.; Wewers, M. D.; Rennard, S. I.; Adelberg, S.; Crystal, Ronald.

In: Journal of Clinical Investigation, Vol. 77, No. 3, 01.01.1986, p. 700-708.

Research output: Contribution to journalArticle

Bitterman, P. B. ; Wewers, M. D. ; Rennard, S. I. ; Adelberg, S. ; Crystal, Ronald. / Modulation of alveolar macrophage-driven fibroblast proliferation by alternative macrophage mediators. In: Journal of Clinical Investigation. 1986 ; Vol. 77, No. 3. pp. 700-708.
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