Epithelial Necrosis and Alveolar Collapse in the Pathogenesis of Usual Interstitial Pneumonia

Myers, Jeffrey L.; Katzenstein, Anna-Luise A.

doi:10.1378/chest.94.6.1309

Cited by 129 publications

(87 citation statements)

References 4 publications

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“…Early ultrastructural studies described damage to the epithelium with reactive epithelial cells (15)(16)(17)(18). More recently, increased apoptosis of type II AECs has been demonstrated both in areas of IPF/UIP that appear histologically normal, without established fibrosis (19), and in epithelial cells overlying myofibroblasts (20).…”

Section: Apoptosis Of Aecs In Ipf What Is the In Vivo Evidence For Apmentioning

confidence: 99%

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Thannickal

Horowitz

2006

Proceedings of the American Thoracic Society

314

263

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Idiopathic pulmonary fibrosis (IPF) is a chronic, relentlessly progressive fibrosing disease of the lung of unknown etiology. Significant progress has been made in recent years in elucidating key aspects of the pathobiology of IPF. Insights into disease pathogenesis have come from studies of cell biology, growth factor/cytokine signaling, animal models of pulmonary fibrosis, and human IPF cells and tissue. A consistent finding in the ultrastructural pathology of IPF is alveolar epithelial cell injury and apoptosis. Another consistent finding in the histopathology of human IPF, described as usual interstitial pneumonia, is the accumulation of aggregates of myofibroblasts in fibroblastic foci. The extent or profusion of fibroblastic foci in lung biopsies is strongly correlated with increased mortality in patients with IPF. There is emerging evidence that myofibroblasts in IPF/usual interstitial pneumonia, both in the in vivo microenvironment and during the process of differentiation in vitro, acquire resistance to apoptosis. Here, we review the current evidence and mechanisms for this apparent "apoptosis paradox" in the pathogenesis of IPF.

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Section: Apoptosis Of Aecs In Ipf What Is the In Vivo Evidence For Apmentioning

confidence: 99%

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Thannickal

Horowitz

2006

Proceedings of the American Thoracic Society

314

263

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“…(6)(7)(8) O diagnóstico de fibrose pulmonar idiopática é freqüen-temente aceito em bases clínicas, porém, para o diagnós-tico definitivo, é necessário biópsia cirúrgica. Os achados histológicos considerados essenciais para o diagnóstico incluem um processo intersticial com distribuição temporal heterogênea, com áreas de pulmão preservado ao lado de outras comprometidas por fibrose, remodelamento do parênquima pulmonar e presença de focos fibroblásti-cos. (3,9,10) As doenças intersticiais em geral teriam como seqüên-cia evolutiva uma inflamação inicial (alveolite) com progressão para fibrose irreversível. Com bases nesses achados, foram feitas propostas de quantificação da extensão da inflamação e da fibrose nas biópsias cirúrgicas.…”

Section: Introductionunclassified

Achados histológicos e sobrevida na fibrose pulmonar idiopática

Coletta¹,

Pereira

Ferreira

et al. 2003

J. Pneumologia

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Background: Idiopathic pulmonary fibrosis was recently redefined as usual interstitial pneumonia of unknown etiology. Consequently, the prognostic value of histological findings needs to be reassessed. Objective: To correlate clinical, functional and histological findings with survival in patients with idiopathic pulmonary fibrosis. Method: Patients (n = 51; mean age: 66 ± 8 years; gender: 21 females/30 males) were evaluated. Of the 51, 26 were smokers or ex-smokers. Duration of symptoms, forced vital capacity and smoking habits were recorded. All patients presented usual interstitial pneumonia verified through histology. Degree of honeycombing, established fibrosis, desquamation, cellularity, myointimal thickening of blood vessels and number of fibroblastic foci were graded according to the semiquantitative method. Results: Median duration of symptoms was 12 months and initial forced vital capacity was 72 ± 21%. Cox multivariate analysis revealed that survival correlated inversely and significantly (p < 0.05) with duration of symptoms and fibroblastic foci score, as well as with myointimal thickening of blood vessels. Limited numbers of fibroblastic foci, as well as myointimal thickening involving less than 50% of blood vessels, were predictive of greater survival. No correlation with survival was found for gender, age, forced vital capacity, inflammation or degree of cellularity. Conclusion: Semiquantitative analysis of lung biopsies yields relevant prognostic information regarding patients with usual interstitial pneumonia.

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“…Although little is known about how the alveolar epithelium is injured, the ensuing fibrotic response is associated with unrestrained accumulation of fibroblasts and myofibroblasts that synthesize and deposit collagen fibrils within fibroblast foci located in the pulmonary parenchyma (2,3). Recent studies have suggested that pulmonary fibroblasts arise by several routes including increased migration and proliferation of resident pulmonary fibroblasts, mesenchymal transition of the alveolar epithelium, and recruitment of bone marrow-derived progenitor cells (4)(5)(6)(7).…”

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confidence: 99%

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

Wynes

Edelman

Kostyk

et al. 2011

The Journal of Immunology

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Idiopathic pulmonary fibrosis (IPF) is associated with the accumulation of collagen-secreting fibroblasts and myofibroblasts in the lung parenchyma. Many mechanisms contribute to their accumulation, including resistance to apoptosis. In previous work, we showed that exposure to the proinflammatory cytokines TNF-α and IFN-γ reverses the resistance of lung fibroblasts to apoptosis. In this study, we investigate the underlying mechanisms. Based on an interrogation of the transcriptomes of unstimulated and TNF-α– and IFN-γ–stimulated primary lung fibroblasts and the lung fibroblast cell line MRC5, we show that among Fas-signaling pathway molecules, Fas expression was increased ∼6-fold in an NF-κB– and p38mapk-dependent fashion. Prevention of the increase in Fas expression using Fas small interfering RNAs blocked the ability of TNF-α and IFN-γ to sensitize fibroblasts to Fas ligation-induced apoptosis, whereas enforced adenovirus-mediated Fas overexpression was sufficient to overcome basal resistance to Fas-induced apoptosis. Examination of lung tissues from IPF patients revealed low to absent staining of Fas in fibroblastic cells of fibroblast foci. Collectively, these findings suggest that increased expression of Fas is necessary and sufficient to overcome the resistance of lung fibroblasts to Fas-induced apoptosis. Our findings also suggest that approaches aimed at increasing Fas expression by lung fibroblasts and myofibroblasts may be therapeutically relevant in IPF.

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Epithelial Necrosis and Alveolar Collapse in the Pathogenesis of Usual Interstitial Pneumonia

Cited by 129 publications

References 4 publications

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

Achados histológicos e sobrevida na fibrose pulmonar idiopática

Increased Cell Surface Fas Expression Is Necessary and Sufficient To Sensitize Lung Fibroblasts to Fas Ligation-Induced Apoptosis: Implications for Fibroblast Accumulation in Idiopathic Pulmonary Fibrosis

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