Idiopathic Pulmonary Fibrosis

Crystal, Ronald G.; Fulmer, Jack D.; Roberts, William C.; Moss, Morton L.; Line, Bruce R.; Reynolds, Herbert Y.

doi:10.7326/0003-4819-85-6-769

Cited by 591 publications

(63 citation statements)

References 137 publications

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“…This process proceeded from an early granulation tissue formation to progressive fibrotic derangements of lung architecture, indicating the irreversible nature of the response. This sequence of events suggests that GM-CSF may induce fibrotic reactions at least in part through causing lung parenchymal injury subsequent to macrophage and eosinophil activation, thus supporting an "injury-fibrosis" theory (32). In addition, GM-CSF may directly stimulate lung stromal cell types to undergo migration and proliferation in this process (33,34).…”

Section: Discussionmentioning

confidence: 73%

Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions.

Xing

Ohkawara²,

Jordana³

et al. 1996

J. Clin. Invest.

205

124

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Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a pleiotropic cytokine whose expression is increased in numerous respiratory diseases, particularly in asthma. However, the role of GM-CSF in the pathogenesis of these conditions in vivo remains unclear. Here, we report the functional activities of GM-CSF highly expressed in rat lung after intrapulmonary transfer of the gene coding for murine GM-CSF by using an adenoviral vector. This high, transient expression of GM-CSF led to the sustained but self-limiting accumulation of eosinophils and macrophages associated with tissue injury in the lung followed by varying degrees of irreversible fibrotic reactions observed in later stages. These results suggest that GM-CSF plays a previously unrealized role in the development of respiratory conditions characterized by eosinophilia, granuloma and/or fibrosis and provide the rationale for targeting this molecule in these diseases. ( J. Clin. Invest. 1996. 97:1102-1110.)

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Section: Discussionmentioning

confidence: 73%

Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions.

Xing

Ohkawara²,

Jordana³

et al. 1996

J. Clin. Invest.

205

124

View full text Add to dashboard Cite

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“…Although little is known about the inciting circumstances which lead to the development of IPF, some information regarding the evolution of this lesion is available (4). An early phase of the disease likely involves an expansion of the population of resident alveolar macrophages (AMs) and the recruitment from peripheral blood of inflammatory cells such as neutrophils and eosinophils.…”

Section: Introductionmentioning

confidence: 99%

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Wilborn¹,

Bailie²,

Coffey³

et al. 1996

J. Clin. Invest.

172

140

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Idiopathic pulmonary fibrosis (IPF) is a progressive disorder characterized by inflammation, fibroblast proliferation, and accumulation of extracellular matrix proteins. Leukotrienes (LTs) are pro-inflammatory and pro-fibrogenic mediators derived from the 5-lipoxygenase (5-LO) pathway of arachidonic acid metabolism. They are thought to play a role in a number of disease processes, but have received relatively little attention in investigations into the pathogenesis of IPF. In this study, we measured the levels of immunoreactive LTs B 4 and C 4 in homogenates of lung tissue obtained from patients with newly diagnosed, untreated IPF, as compared to levels measured in homogenates of uninvolved nonfibrotic lung tissue from patients undergoing resectional surgery for bronchogenic carcinoma. Compared to homogenates of nonfibrotic control lung, homogenates from IPF patients contained 15-fold more LTB 4 and 5-fold more LTC 4 . IPF homogenate levels of LTB 4 were significantly correlated with histologic indices of both inflammation ( r ϭ 0.861) and fibrosis ( r ϭ 0.926). Activation of 5-LO is known from in vitro studies to be associated with localization of the enzyme at the nuclear membrane. Immunohistochemical staining for 5-LO protein in alveolar macrophages (AMs) demonstrated that such an "activated" localization pattern was significantly more frequent in IPF lung (19.2 Ϯ 3.3% of cells) than in control lung (9.3 Ϯ 0.9%); this localization pattern was rarely seen (3.2%) in sections from a truly normal transplant donor lung. Consistent with these data, AMs obtained from IPF patients by bronchoalveolar lavage, purified by adherence, and cultured in the absence of a stimulus for 16 h elaborated significantly greater amounts of LTB 4 and LTC 4 than did control AMs obtained from normal volunteers. These data indicate that the 5-LO pathway is constitutively activated in the lungs of patients with IPF, and the AM represents at least one cellular source of LT overproduction in this disorder. We speculate that LTs participate in the pathogenesis of IPF, and their overproduction in this disorder may be amenable to specific pharmacotherapy. (

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“…Occupational exposure to mineral dusts can lead to pulmonary fibrosis [1]. The pathogenesis of lung fibrosis involves highly complicated processes of intercellular communication by peptides released from and to various immune cells and lung target cells in a phenomenon appropriately referred to as "cytokine network" [2].…”

mentioning

confidence: 99%

Plasma levels of soluble tumour necrosis factor receptors are increased in coal miners with pneumoconiosis

Schins¹,

Borm²

1995

Eur Respir J

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P Pl la as sm ma a l le ev ve el ls s o of f s so ol lu ub bl le e t tu um mo ou ur r n ne ec cr ro os si is s f fa ac ct to or r r re ec ce ep pt to or rs s a ar re e i in nc cr re ea as se ed d i in n c co oa al l m mi in ne er rs s w wi it th h p pn ne eu um mo oc co on ni io os si is s ABSTRACT: Among other cytokines, tumour necrosis factor (TNF)-α is considered to play a key role in the development of mineral dust related fibrosis. Previously, we showed that ex-vivo release of TNF by peripheral blood monocytes is a marker for progression of coal workers' pneumoconiosis (CWP). Since soluble TNF receptors (sTNF-Rs) are believed to play an important regulatory role in systemic effects of TNF, we measured plasma levels of sTNF-R55 and sTNF-R75 in coal miners with (n=28) or without (n=76) CWP and in nonexposed controls (n=29).sTNF-R75 levels were significantly increased in miners with CWP (2.09±0.44 ng·mL -1 ) versus the nonexposed controls (1.86±0.23 ng·mL -1 ). Neither sTNF-R55 nor sTNF-R75 were related to exposure, stage of pneumoconiosis, smoking, or (spontaneous or ex-vivo induced) monocyte TNF-release. sTNF-R55 was increased in subjects with medication (especially those using cardiovascular drugs); upon exclusion of these subjects, sTNF-R55 was found also to be significantly increased in CWP.In conclusion, bearing in mind a confounding effect of medication, soluble TNF receptors are elevated in plasma of retired miners with coal workers' pneumoconiosis. These observations further support the important role of TNF-mediated pathways in the pathogenesis of mineral dust related fibrosis.

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Idiopathic Pulmonary Fibrosis

Cited by 591 publications

References 137 publications

Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions.

Transfer of granulocyte-macrophage colony-stimulating factor gene to rat lung induces eosinophilia, monocytosis, and fibrotic reactions.

Constitutive activation of 5-lipoxygenase in the lungs of patients with idiopathic pulmonary fibrosis.

Plasma levels of soluble tumour necrosis factor receptors are increased in coal miners with pneumoconiosis

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