Role of various imbalances centered on alveolar epithelial cell/fibroblast apoptosis imbalance in the pathogenesis of idiopathic pulmonary fibrosis

Wang, Qing; Xie, Zhaoliang; Wu, Qi; Jin, Zhixian; Feng, Jing

doi:10.1097/cm9.0000000000001288

Cited by 12 publications

(23 citation statements)

References 173 publications

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“…IPF also exhibits histological features of UIP/IPF pattern characterized by dense fibrosis causing architecture remodeling with frequent honeycombing, patchy lung involvement by fibrosis, subpleural and/or paraseptal distribution, fibroblast foci at the edge of dense scars (Spagnolo et al, 2018;Baratella et al, 2021). With extensive basic and clinical research on the pathogenesis of IPF in recent years, some potential therapeutic targets have been discovered (Wang et al, 2021). A large number of these targets are growth factors, cytokines, and their signaling pathways, including TGF-β, CTGF, IL-13, CCL-2, leukotriene receptor, lipid proinflammatory mediators, and their downstream signaling.…”

Section: Introductionmentioning

confidence: 99%

Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis

Liu

et al. 2022

Front. Pharmacol.

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Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial lung disease of unknown origin that usually results in death from secondary respiratory failure within 2–5 years of diagnosis. Recent studies have identified key roles of cytokine and growth factor pathways in the pathogenesis of IPF. Although there have been numerous clinical trials of drugs investigating their efficacy in the treatment of IPF, only Pirfenidone and Nintedanib have been approved by the FDA. However, they have some major limitations, such as insufficient efficacy, undesired side effects and poor pharmacokinetic properties. To give more insights into the discovery of potential targets for the treatment of IPF, this review provides an overview of cytokines, growth factors and their signaling pathways in IPF, which have important implications for fully exploiting the therapeutic potential of targeting cytokine and growth factor pathways. Advances in the field of cytokine and growth factor pathways will help slow disease progression, prolong life, and improve the quality of life for IPF patients in the future.

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Section: Introductionmentioning

confidence: 99%

Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis

Liu

et al. 2022

Front. Pharmacol.

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“…It has been previously reported that apoptosis is increased in alveolar epithelial cells of patients with IPF but decreased in myofibroblasts, 27 with this imbalance contributing to IPF pathogenesis. 28 Furthermore, the use of therapies that can selectively manipulate apoptosis have been proposed. 29 Additionally, genetic variants within cell cycle genes have been shown to be associated with IPF development and progression.…”

Section: Discussionmentioning

confidence: 99%

Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis

Kraven

Taylor

Molyneaux

et al. 2022

Thorax

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BackgroundConsiderable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes.MethodsWe co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases).FindingsWe identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10−5).InterpretationWe have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

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“…Among the biological pathways that were significantly enriched for Cluster 2 were pathways related to apoptosis and cell cycle. It has been previously reported that apoptosis is increased in alveolar epithelial cells of IPF patients but decreased in myofibroblasts (23), with this imbalance contributing to IPF pathogenesis (24). Furthermore, the use of therapies that can selectively manipulate apoptosis have been proposed (25).…”

Section: Discussionmentioning

confidence: 99%

“…It has been previously reported that apoptosis is increased in alveolar epithelial cells of IPF patients but decreased in myofibroblasts, 23 with this imbalance contributing to IPF pathogenesis. 24 Furthermore, the use of therapies that can selectively manipulate apoptosis have been proposed. 25 Additionally, genetic variants within cell cycle genes have been shown to be associated with IPF development and progression.…”

Section: Discussionmentioning

confidence: 99%

Cluster analysis of transcriptomic datasets to identify endotypes of Idiopathic Pulmonary Fibrosis

Kraven

Taylor

Molyneaux

et al. 2021

Preprint

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Rationale: Considerable clinical heterogeneity in Idiopathic Pulmonary Fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes could allow for a biomarker-driven personalised medicine approach in IPF. Objectives: To improve our understanding of the pathogenesis of IPF by identifying clinically distinct groups of patients with IPF that could represent distinct disease endotypes. Methods: We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases). Measurements and main results: We identified three clusters of IPF patients with statistically significant differences in lung function (P=0.009) and mortality (P=0.009) between groups. Gene enrichment analysis implicated dysregulation of mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: hazard ratio= 4.25, 95% confidence interval= [2.14, 8.46], P=3.7×10-5). Conclusions: We have identified blood gene expression signatures capable of discerning groups of IPF patients with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.

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Role of various imbalances centered on alveolar epithelial cell/fibroblast apoptosis imbalance in the pathogenesis of idiopathic pulmonary fibrosis

Cited by 12 publications

References 173 publications

Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis

Targeting Growth Factor and Cytokine Pathways to Treat Idiopathic Pulmonary Fibrosis

Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis

Cluster analysis of transcriptomic datasets to identify endotypes of Idiopathic Pulmonary Fibrosis

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