Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling

Chambers, Rachel C.

doi:10.1183/09059180.00010905

Cited by 29 publications

(25 citation statements)

References 58 publications

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“…Possible explanations for our finding include 1) IPF increasing the risk of VTE, and 2) a prothrombotic state leading to the development of IPF and VTE. This study supports the hypothesis that activation of the coagulation cascade may be involved in the pathogenesis of IPF [2,7]. …”

supporting

confidence: 78%

Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population-based study

et al. 2014

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supporting

confidence: 78%

Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population-based study

et al. 2014

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“…3). PAI-1 is upregulated in late stage SSc-PF and is known to be important in pulmonary fibrosis [73–75]. One mechanism by which fibrinolysis may contribute to the resolution of fibrosis is through the induction of fibroblast apoptosis [76].…”

Section: Discussionmentioning

confidence: 99%

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

et al. 2017

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BackgroundSystemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.MethodsWe used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast the skin and lung microenvironments and to assess the functional role of the inflammatory and fibrotic genes in each organ. Lastly, we tested the expression of macrophage activation state-associated gene sets for enrichment in skin and lung using a Wilcoxon rank sum test.ResultsWe identified a common pathogenic gene expression signature—an immune–fibrotic axis—indicative of pro-fibrotic macrophages (MØs) in multiple tissues (skin, lung, esophagus, and peripheral blood mononuclear cells) affected by SSc. While the co-expression of these genes is common to all tissues, the functional consequences of this upregulation differ by organ. We used this disease-associated signature to query tissue-specific functional genomic networks to identify common and tissue-specific pathologies of SSc and related conditions. In contrast to skin, in the lung-specific functional network we identify a distinct lung-resident MØ signature associated with lipid stimulation and alternative activation. In keeping with our network results, we find distinct MØ alternative activation transcriptional programs in SSc-associated PF lung and in the skin of patients with an “inflammatory” SSc gene expression signature.ConclusionsOur results suggest that the innate immune system is central to SSc disease processes but that subtle distinctions exist between tissues. Our approach provides a framework for examining molecular signatures of disease in fibrosis and autoimmune diseases and for leveraging publicly available data to understand common and tissue-specific disease processes in complex human diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-017-0417-1) contains supplementary material, which is available to authorized users.

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“…Studies have demonstrated that PAR-1 is highly expressed on cells implicated in fibrosis in the lungs of people with IPF,32 suggesting the receptor plays an important role in the pathogenic process. Activation of PAR-1 receptors leads to the induction and release of potent profibrotic35 and proinflammatory mediators,5 induces differentiation of fibroblasts to myofibroblasts36 and promotes extracellular matrix protein production 37. Furthermore, active inhibition of the clotting cascade using nebulised heparin, urokinase or activated protein C reduces collagen accumulation and the development of fibrotic lesions in experimental models of lung fibrosis 38 39…”

Section: Discussionmentioning

confidence: 99%

Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case–control study

Navaratnam

Fogarty

McKeever

et al. 2013

Thorax

103

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Background Laboratory studies suggest that the clotting cascade is activated in fibrotic lungs. Since humans vary in their tendency to clot due to a variety of inherited or acquired defects, we investigated whether a prothrombotic state increases the chance of developing idiopathic pulmonary fibrosis (IPF) and/or worsens the prognosis of IPF. Methods We recruited 211 incident cases of IPF and 256 age-and sex-matched general population controls and collected data on medical history, medication, smoking habit, blood samples as well as lung function and high-resolution CT scans done as part of routine clinical care. A prothrombotic state was defined as the presence of at least one inherited or acquired clotting defect or marker of fibrinolytic dysfunction. We used logistic regression to quantify the association between a prothrombotic state and IPF adjusted for age, sex, smoking habit and highly sensitive C reactive protein.Cox regression was used to determine the influence of a prothrombotic state on survival. Results Cases were more than four times more likely than controls to have a prothrombotic state (OR 4.78, 95% CI 2.93 to 7.80; p<0.0001). Cases with a prothrombotic state were also likely to have more severe disease (forced vital capacity <70% predicted) at presentation (OR 10.79, 95% CI 2.43 to 47.91) and had a threefold increased risk of death (HR 3.26, 95% CI 1.09 to 9.75). Conclusions People with IPF are more likely to have a prothrombotic state than general population controls and the presence of a prothrombotic state has an adverse impact on survival.

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Abnormal wound healing responses in pulmonary fibrosis: focus on coagulation signalling

Cited by 29 publications

References 58 publications

Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population-based study

Venous thromboembolism in people with idiopathic pulmonary fibrosis: a population-based study

A novel multi-network approach reveals tissue-specific cellular modulators of fibrosis in systemic sclerosis

Presence of a prothrombotic state in people with idiopathic pulmonary fibrosis: a population-based case–control study

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