Fibronectin in human bronchopulmonary lavage fluid. Elevation in patients with interstitial lung disease.

Self Cite

213

108

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 spontaneously 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 y (IFNy), 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. IFNy had no effect on fibroblast replication. In contrast, PGE2 resulted in a dose-dependent inhibition offibroblast 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 GI phase of the cell cycle. These data indicate that lung fibroblast replication in response to two of the primary growth promoting signals spontaneously released by alveolar macrophages in the interstitial lung disorders, while uninfluenced by IFNy, 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.

Section: Discussionmentioning

confidence: 99%

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

Bitterman¹,

Wewers²,

Rennard³

et al. 1986

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213

108

“…However, in contrast to mRNA levels, the fibronectin levels in the BAL did not decline in the later times (Raghow, R., unpublished observations). Increased levels of fibronectin in the BAL fluid have been observed in patients with interstitial pulmonary fibrosis (15). The apparent discordance between the levels of mRNA and protein suggests that posttranscriptional regulatory mechanisms may also be operative.…”

Section: Discussionmentioning

confidence: 99%

“…In addition to changes in the cellular composition, there are also characteristic changes in the composition of extracellular matrix (2); increased net synthesis and/or deposition of interstitial collagens (3)(4)(5)(6)(7), elastin (8,9), and proteoglycans (10,11,12) in the lungs have been reported in experimentally induced pulmonary fibrosis. There are several reports of an increased collagen content of fibrotic lungs in humans (2,13,14); a recent study also reported increased levels of fibronectin in the bronchoalveolar lavage fluid ofhuman lungs from patients suffering from idiopathic pulmonary fibrosis (15). The exact relationship between altered extracellular matrix and concomitant changes in the cellular composition in the lungs undergoing fibrosis is unclear.…”

Section: Introductionmentioning

confidence: 99%

Profiles of steady state levels of messenger RNAs coding for type I procollagen, elastin, and fibronectin in hamster lungs undergoing bleomycin-induced interstitial pulmonary fibrosis.

Raghow¹,

Lurie²,

Seyer³

et al. 1985

126

We have characterized the messenger RNAs (mRNAs) coding for procollagen al(I), elastin, fibronectin, and actin in the lungs of Syrian golden hamsters by Northern blot analyses. While elastin, fibronectin, and ,B-actin were each coded for by a single mRNA species of 4.1 kilobases (kb), 9.1 kb, and 2.1 kb in size, respectively, we identified a major (5.4 kb) and a minor (6.5 kb) procollagen al(I) mRNA species in the hamster lungs.The mRNAs for the three extracellular matrix proteins showed increased accumulation followed by steady decline in the bleomycin-treated lungs. There were significant differences among the three mRNAs in the relative increase and the time of maximum accumulation. After reaching the peak levels between 2-3 wk posttreatment, the levels of procollagen al(I) and elastin mRNAs declined to near normal values around the fourth week. In contrast, the accumulation of fibronectin mRNA was maximum in the first week after bleomycin treatment. The procollagen al(I) mRNA accumulated most dramatically (sevenfold above the levels in the untreated animals) compared with a fivefold increase in mRNA coding for fibronectin. Elastin mRNA increased approximately twofold above the control values. Nuclear runoff transcription experiments demonstrated a selective increase in the rates of transcription of genes coding for procollagen al(I), fibronectin, and elastin; the extent of transcriptional stimulation of procollagen al(I) and fibronectin genes was significantly greater than that of elastin. Since the amount of actin mRNA, as well as the rate of transcription of actin gene(s), varied only slightly after bleomycin treatment, we conclude that the metabolism of mRNAs coding for extracellular matrix proteins may be preferentially perturbed during pulmonary fibrosis.

“…Several studies have demonstrated that alveolar macrophages synthesize and secrete fibronectin and that alveolar macrophages associated with chronic inflammatory diseases of the lower respiratory tract secrete exaggerated amounts of this molecule (6)(7)(8). In the context of the known functions of fibronectin, it is likely that it represents one of the alveolar macrophage mediators that plays a role in both defending the lung and in modulating the damage and repair that accompanies inflammatory processes in the lower respiratory tract (6)(7)(8)(9)(10)(11)(12)(13)(14).…”

Section: Introductionmentioning

confidence: 99%

Modulation of fibronectin gene expression in human mononuclear phagocytes.

Yamauchi

Martinet²,

Crystal³

1987

Self Cite

Under some conditions, mononuclear phagocytes spontaneously synthesize and release fibronectin, an extracellular matrix glycoprotein with versatile effects on cell-matrix interactions. To gain insight into the processes that modulate the level of fibronectin secretion by these cells, we used monocytes, in vitro matured nonocytes and alveolar macrophages as models to compare fibronectin mRNA levels and fibronectin secretion in a variety of circumstances. Using Northern analysis and dot-blot analysis with a 32P-labeled human fibronectin cDNA probe, we evaluated steady-state mRNA levels and a human fibronectin-specific ELISA was used to evaluate fibronectin secretion. In all cases the amounts of fibronectin secreted paralleled fibronectin mRNA levels. Specifically (a) when fibronectin mRNA was undetectable, as in the case of normal blood monocytes, no fibronectin was secreted, but whenever fibronectin mRNA was present, as in normal alveolar macrophages, fibronectin was secreted by the cells; (b) as monocytes matured into macrophages in vitro, the cells began to express fibronectin mRNA and the cells secreted fibronectin; (c) when alveolar macrophages were activated with surface stimuli such as lipopolysaccharide (LPS) or immune complexes, fibronectin mRNA levels decreased and in parallel, the cells secreted less fibronectin; (d) in idiopathic pulmonary fibrosis (IPF), alveolar macrophages contained severalfold more fibronectin mRNA transcripts that normal and the cells spontaneously secreted severalfold more fibronectin than normal; and (e) when IPF alveolar macrophages were placed in culture the fibronectin mRNA levels in the cells decreased with time, and concurrently the amounts of fibronectin produced per unit time continually decreased. The observation of a strict concordance of fibronectin mRNA levels and fibronectin release by mononuclear phagocytes suggests that, at least in many circumstances, fibronectin secretion by mononuclear phagocytes is controlled by steady-state levels of fibronectin mRNA.