Acute lung injury. Pathogenesis of intraalveolar fibrosis.

Snyder, Linda; Hertz, Marshall I.; Peterson, Mark S.; Harmon, Keith R.; Marinelli, William A.; Henke, Craig A.; Greenheck, J.; Chen, Baruch; Bitterman, Peter B.

doi:10.1172/jci115351

Cited by 91 publications

(47 citation statements)

References 46 publications

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“…Strong evidence points away from TNF-␣ as a major modulator of fibroblast phenotype in early ALI, despite its abundance. In contrast, prior work provides convincing evidence for an alveolar mitogenic predominance and a fibroblast mitogenic role for PDGF B chain-related molecules in early (within 3 days) ALI bronchoalveolar lavage fluid (21,55). IL-1␤ can also up-regulate PDGF A chain and PDGFR-␣ in fibroblasts, thereby potentially sensitizing fibroblasts to the mitogenic effects of PDGF (56,57).…”

Section: Discussionmentioning

confidence: 93%

“…In human acute lung injury, PDGF-related molecules (B chain isoforms) have been identified as one group of mitogens for fibroblasts in the alveolar compartment (21). However, prior work was largely accomplished using samples (bronchoalveolar lavage) that are 100-fold diluted relative to alveolar lining fluid in vivo and that were collected several days after the onset of clinical acute lung injury.…”

mentioning

confidence: 99%

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Pulmonary Edema Fluid from Patients with Early Lung Injury Stimulates Fibroblast Proliferation through IL-1β-Induced IL-6 Expression

Olman

White²,

Ware

et al. 2004

The Journal of Immunology

121

103

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Although the fibroproliferative response to lung injury occurs with a high frequency in patients with clinical acute lung injury, the mechanisms that initiate this response are largely unknown. This study was undertaken first to identify fibroblast mitogenic factors in pulmonary edema fluid, and second to examine the human lung fibroblast’s gene expression profile in response to pulmonary edema fluid. The edema fluid obtained from patients with early lung injury has an eightfold higher concentration of IL-1β and a twofold greater IL-1β-dependent mitogenic effect than does fluid obtained from control patients with hydrostatic pulmonary edema. Furthermore, fibroblasts responded to acute lung injury patient-derived edema fluid through production of soluble mediators that possess an autocrine mitogenic effect. Gene array analysis reveals that acute lung injury edema fluid induces several inflammation-modulating and proliferation-related genes in fibroblasts, whose inductions are similarly dependent on bioactive IL-1β. Most notably, the 20-fold induction of IL-6 mRNA and protein was completely blocked by IL-1 receptor antagonist. The combined addition of IL-1β and IL-6 was mitogenic, and the proliferative response to conditioned medium from IL-1β-exposed cells was blocked by antagonistically acting Abs to IL-6 or to gp130. These novel findings indicate that soluble IL-1β bioactivity and autocrine IL-1β-dependent IL-6 up-regulation are critical initiators of fibroblast activation and proliferation and that they likely play a role in the fibroproliferative response seen in human acute lung injury.

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Section: Discussionmentioning

confidence: 93%

mentioning

confidence: 99%

Pulmonary Edema Fluid from Patients with Early Lung Injury Stimulates Fibroblast Proliferation through IL-1β-Induced IL-6 Expression

Olman

White²,

Ware

et al. 2004

The Journal of Immunology

121

103

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“…PDGF and TGF-␣ are both elevated in alveolar macrophages or bronchoalveolar lavage fluid from patients with pulmonary fibrosis. 8,9,11,28 In rat models of fibrosis, PDGF and the PDGF ␣-receptor subtype are increased 2 to 3 days after lung injury by bleomycin or metals. 4,29 EGF and TGF-␣ are elevated 2 to 4 days in the rat bleomycin model.…”

Section: Discussionmentioning

confidence: 99%

Specific Inhibitors of Platelet-Derived Growth Factor or Epidermal Growth Factor Receptor Tyrosine Kinase Reduce Pulmonary Fibrosis in Rats

Rice

Moomaw

Morgan

et al. 1999

The American Journal of Pathology

135

107

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The proliferation of myofibroblasts is a central feature of pulmonary fibrosis. In this study we have used tyrosine kinase inhibitors of the tyrphostin class to specifically block autophosphorylation of the platelet-derived growth factor receptor (PDGF-R) or epidermal growth factor receptor (EGF-R). AG1296 specifically inhibited autophosphorylation of PDGF-R and blocked PDGF-stimulated [ 3 H]thymidine uptake by rat lung myofibroblasts in vitro. AG1478 was demonstrated as a selective blocker of EGF-R autophosphorylation and inhibited EGF-stimulated DNA synthesis in vitro. In a rat model of pulmonary fibrosis caused by intratracheal instillation of vanadium pentoxide (V 2 O 5 ) , intraperitoneal delivery of 50 mg/kg AG1296 or AG1478 in dimethylsulfoxide 1 hour before V 2 O 5 instillation and again 2 days after instillation reduced the number of epithelial and mesenchymal cells incorporating bromodeoxyuridine (Brdu) by ϳ50% at 3 and 6 days after instillation. V 2 O 5 instillation increased lung hydroxyproline fivefold 15 days after instillation , and AG1296 was more than 90% effective in preventing the increase in hydroxyproline , whereas AG1478 caused a 50% to 60% decrease in V 2 O 5 -stimulated hydroxyproline accumulation. These data provide evidence that PDGF and EGF receptor ligands are potent mitogens for collagen-producing mesenchymal cells during pulmonary fibrogenesis , and targeting tyrosine kinase receptors could offer a strategy for the treatment of fibrotic lung diseases. (Am J Pathol 1999, 155:213-221)

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“…FABISIAK et al [61] examined expression of PDGF-B mRNA in the rat lung during chronic hyperoxia, and showed that increased expression of this gene was temporally self-limited. Furthermore, the role of PDGF in patients with adult respiratory distress syndrome (ARDS) is inconclusive [62]. Thus, whilst PDGF probably plays a reparative role after injury, its involvement in the development of fibrosis is much less certain.…”

Section: Growth Factorsmentioning

confidence: 99%

Immune-inflammatory functions of fibroblasts

Jordana¹,

Särnstrand²,

Sime³

et al. 1994

Eur Respir J

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Inflammation is a response that has evolved over millions of years to become an extremely complex process. This complexity reflects the host's need to deal effectively with a wide variety of potentially injurious agents, as well as the need to incorporate an adequate set of checks and balances. An inappropriately checked response, which occurs rarely, results in disease, either acute or chronic. However, in most instances, inflammation is a beneficial response, essential for survival. Inflammation comprises an extensive network of cellular interactions implemented by an overwhelming number of molecules. One category of signal includes soluble products, such as neuropeptide, lipid mediators, cytokines and growth factors, most of which can be produced by inflammatory/haemopoietic cells. However, resident structural cells can also produce many of these products and, on this basis only, fibroblasts, epithelial, endothelial and smooth muscle cells should be considered as active contributors to the regulation of the inflammatory response. Extracellular matrix (ECM) proteins comprise another category of signals. Whilst the most recognized activities of these proteins are those concerned with providing structural tissue integrity, it is clear that they also have powerful inductive effects. Indeed, ECM proteins can influence the shape, movement and state of activation of inflammatory cells in the tissue. Recent evidence indicates that these signals may also play substantial roles in homing of inflammatory cells to certain sites and in the handling of a number of cytokines and growth factors. In so far as fibroblasts are the main producers of ECM proteins, these new data establish an indirect but important role for fibroblasts in the regulation of the inflammatory response.

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Acute lung injury. Pathogenesis of intraalveolar fibrosis.

Cited by 91 publications

References 46 publications

Pulmonary Edema Fluid from Patients with Early Lung Injury Stimulates Fibroblast Proliferation through IL-1β-Induced IL-6 Expression

Pulmonary Edema Fluid from Patients with Early Lung Injury Stimulates Fibroblast Proliferation through IL-1β-Induced IL-6 Expression

Specific Inhibitors of Platelet-Derived Growth Factor or Epidermal Growth Factor Receptor Tyrosine Kinase Reduce Pulmonary Fibrosis in Rats

Immune-inflammatory functions of fibroblasts

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