Contribution of epithelial-to-mesenchymal transition to phenotypic changes in idiopathic interstitial pneumonias
Guðmundur H. GuðmundssonBryndís ValdimarsdóttirAri Jón ArasonMagnús K. MagnússonHelgi J. ÍsakssonÞórarinn Guðjónsson
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Abstract:
Idiopathic interstitial pneumonias cause fibrosis in which lungs become scarred due to the increase number of myofibroblasts and excess extracellular matrix deposition. Structural alterations in the interstitium of lung parenchyma are associated with significant mortality and morbidity. Epithelial-to-mesenchymal transition (EMT) is a process whereby epithelial cells undergo transition to a mesenchymal phenotype. This process has been shown to contribute to idiopathic pulmonary fibrosis (IPF) but contribution to nonspecific interstitial pneumonitis (NSIP) is unknown We investigated whether EMT was present in patients with IPF (n = 10) or NSIP (n = 6), using immunohistochemistry and confocal microscopy. All patients had surgical lung biopsies. Normal lung tissue obtained from lobectomies was also evaluated.We performed immunostaining for E-cadherin, p63, CK14 and the signature EMT markers N-cadherin and Vimentin. In addition we performed immunofluorecent staining for N-cadherin, p63 and Vimentin. We show that p63 positive basal cells are present in the overlying epithelium adjacent to fibrotic foci in IPF. This basal epithelium has acquired increased mesenchymal markers (N-cadherin,Vimentin) and increased CK14 while retaining E-cadherin expression. The underlying fibrotic foci showed both E- and N-cadherin positive cells.Samples from patients with NSIP had much less responses to CK14, Vimentin, p63 and N-cadherin than patients with IPF. This was related to fewer numbers of fibroblastic foci. Cells positive for p63 were found in alveoli and terminal bronchioles in NSIP but not normal controls. Results suggest that EMT is differently involved in pathogenesis of IPF than NSIP.Keywords:
Myofibroblast
Usual interstitial pneumonia
Keratin 8
Pirfenidone
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Idiopathic pulmonary fibrosis (IPF) is a genetically mediated, age-associated, progressive form of pulmonary fibrosis characterised pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (non-IPF UIP), whose clinical course is similarly poor, suggesting common molecular drivers. This study investigates whether IPF and non-IPF UIP lungs similarly express markers of telomere dysfunction and senescence.To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissues from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Histopathological changes in both IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci, and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, non-caseating granulomas, airway-centred inflammation, or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs than in those of age-similar, unused donor, controls. Levels of molecular markers of senescence (p16 and p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localised expression of these proteins to AECII cells. The mucin 5B (MUC5B) gene promoter variant minor allele frequency was similar between IPF and non-IPF UIP patients, and MUC5B expression was similar in IPF and non-IPF UIP lungs.Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the clinical diagnosis.
Usual interstitial pneumonia
Honeycombing
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Background: Although classified as a rare disease, the global burden of disease study reports showed that interstitial lung disease is ranked 40th in the diseases with high mortality, and its prevalence had increased by 86% since 1990. The most common interstitial lung disease”idiopathic pulmonary fibrosis (IPF)”has low survival rates”2-3 years after diagnosis”and is irreversible. Establishing a definite diagnosis of IPF is very difficult because it needs a multidisciplinary approach, as an establishment based on the description of HRCT and lung biopsy is needed. The goal of therapy is to prevent the progression of fibrosis. Case: We report a case of an adult woman, 46 years old with idiopathic pulmonary fibrosis (IPF) with Probable Usual Interstitial Pneumonia (UIP) pattern at dr. Saiful Anwar Hospital. History taking, physical examination and laboratory and chest Xray examination of the patient found a suspicion of ILD. CT-scan showed fibrosis in both lungs, honeycomb appearance with pulmonary bronchiectasis traction, which fit the description of IPF, and thus suspended the diagnosis of ILD. VATS pulmonary biopsy confirmed the diagnosis of IPF. The patient experienced a decrease in clinical conditions, as her complaint was worsening in the last month, in accordance to the state of acute exacerbations. Conclusion: In this patient, the diagnosis of IPF with Probable UIP pattern was made through a multidisciplinary approach, including the pulmonology, radiology and anatomical pathology department. Keywords: IPF, IPF, Probable UIP Pattern, IPF Diagnosis
Usual interstitial pneumonia
Lung biopsy
Pulmonology
Pirfenidone
Idiopathic interstitial pneumonia
Cryptogenic Organizing Pneumonia
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Idiopathic aspiratory fibrosis (IPF) is the most well-known sort of idiopathic interstitial pneumonia (IIP). IIPs are precipitously shappening (idiopathic) diffuse parenchymal lung illnesses. IPF is characterized as a precipitouly happening (idiopathic) explicit type of persistent fibrosing interstitial pneumonia restricted to the lung and related with an example of Usual Interstitial Pneumonia (UIP) on imaging or histology. Pleasant rules for the analysis of Interstitial Lung Disease (ILD), preceding thought for against fibrotic treatment, specify that the conclusion of ILD has been made by a multidisciplinary group (MDT).
Idiopathic interstitial pneumonia
Usual interstitial pneumonia
Diffuse alveolar damage
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Idiopathic pulmonary fibrosis (IPF; also known as cryptogenic fibrosing alveolitis) is a distinctive type of chronic fibrosing interstitial pneumonia of unknown cause associated with the histological pattern usual interstitial pneumonia (UIP). UIP is a distinct histological pattern observed in IPF but may also be found in other etiologies. The diagnosis of UIP can be established by surgical lung biopsy or by high-resolution thin-section CT scans (provided the radiographic features are classical). Historically, patients labeled as 'IPF' encompassed a group of disorders, including UIP, as well as other idiopathic interstitial pneumonias, which differ from UIP in prognosis and responsiveness to therapy. The term IPF should be restricted to patients with idiopathic UIP. The inciting cause(s) and pathogenesis of IPF have not been elucidated but alveolar epithelial cell injury and dysregulation or altered phenotypic expression of fibroblasts are key elements. Inflammatory cells may play minor roles in initiating or propagating the fibrotic process. The prognosis of idiopathic UIP is poor. Mean survival following diagnosis approximates at 3 years. Current medical therapies are of unproven value. Lung transplantation is a viable option for patients failing medical therapy.
Usual interstitial pneumonia
Idiopathic interstitial pneumonia
Etiology
Cryptogenic Organizing Pneumonia
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Recent studies have suggested that in patients with an idiopathic interstitial pneumonia (IIP), a probable usual interstitial pneumonia (UIP) pattern on chest computed tomography (CT) is sufficient to diagnose idiopathic pulmonary fibrosis (IPF) without histopathology.We retrospectively compared the prognosis and time to first acute exacerbation (AE) in IIP patients with a UIP and a probable UIP pattern on initial chest CT.One hundred and sixty IIP patients with a UIP pattern and 242 with a probable UIP pattern were identified. Probable UIP pattern was independently associated with longer survival time (adjusted hazard ratio 0.713, 95% CI 0.536-0.950; p=0.021) and time to first AE (adjusted hazard ratio 0.580, 95% CI 0.389-0.866; p=0.008). In subjects with a probable UIP pattern who underwent surgical lung biopsy, the probability of a histopathological UIP pattern was 83%. After multidisciplinary discussion and the inclusion of longitudinal behaviour, a diagnosis of IPF was made in 66% of cases. In IPF patients, survival time and time to first AE were not associated with CT pattern. Among subjects with a probable UIP pattern, compared to non-IPF patients, survival time and time to first AE were shorter in IPF patients.In conclusion, IIP patients with a probable UIP pattern on initial chest CT had a better prognosis and longer time to first AE than those with a UIP pattern. However, when baseline data and longitudinal behaviour provided a final diagnosis of IPF, CT pattern was not associated with these outcomes. This suggests diagnostic heterogeneity among patients with a probable UIP pattern.
Usual interstitial pneumonia
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Pirfenidone
Nintedanib
Usual interstitial pneumonia
Lung biopsy
Honeycombing
Idiopathic interstitial pneumonia
Reticular connective tissue
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Background: Idiopathic pulmonary fibrosis (IPF) is an age-associated, progressive form of pulmonary fibrosis characterized pathologically by a usual interstitial pneumonia (UIP) pattern of fibrosis. The UIP pattern is also found in pulmonary fibrosis attributable to clinical diagnoses other than IPF (Non-IPF UIP) whose clinical course is similarly poor, suggesting common molecular drivers. Methods: To test whether patients with IPF and non-IPF UIP share molecular drivers, lung tissue from 169 IPF patients and 57 non-IPF UIP patients were histopathologically and molecularly compared. Results: Histopathologic changes in IPF and non-IPF UIP patients included temporal heterogeneity, microscopic honeycombing, fibroblast foci and dense collagen fibrosis. Non-IPF UIP lungs were more likely to have lymphocytic infiltration, noncaseating granulomas, airway centered inflammation or small airways disease. Telomeres were shorter in alveolar type II (AECII) cells of both IPF and non-IPF UIP lungs compared to age-similar, unused donor, controls. Telomere shortening was isolated to AECII cells when comparing telomere lengths between AECII and adjacent cells in individual patients. Molecular markers of senescence (p16, p21) were elevated in lysates of IPF and non-IPF UIP lungs. Immunostaining localized expression of these proteins to AECII cells. Conclusions: Molecular markers of telomere dysfunction and senescence are pathologically expressed in both IPF and non-IPF UIP lungs. These findings suggest that common molecular drivers may contribute to the pathogenesis of UIP-associated pulmonary fibrosis, regardless of the underlying clinical context.
Usual interstitial pneumonia
Honeycombing
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Acute exacerbations (AEs) of idiopathic pulmonary fibrosis (IPF) and other idiopathic interstitial pneumonia (IIP) have a poor prognosis. This study aims to clarify the incidence and prognosis of AE in IPF and the other IIP.A total of 229 patients were enrolled, of whom 92 had IPF and 137 had 'IIP other than IPF' based on the American Thoracic Society/European Respiratory Society/Japanese Respiratory Society/Latin American Thoracic Association (ATS/ERS/JRS/ALAT) 2011 IPF Guidelines. IIP other than IPF included 11 patients with a surgical lung biopsy (SLB) and the remainder without such a biopsy. IIP other than IPF was further classified into IIP with a 'possible usual interstitial pneumonia (UIP)' pattern on HRCT (n = 75) and IIP with 'inconsistent with UIP' pattern (n = 62) based on published guidelines. Predictors of AE and the prognosis after AE were examined in these groups.The 1-year incidence of AE in IPF, IIP with possible UIP HRCT patterns and IIP with inconsistent with UIP HRCT patterns was 16.5%, 8.9% and 4.0%, respectively. AE occurred significantly more frequently in IPF than in IIP with possible UIP and inconsistent with UIP HRCT patterns after adjustment for BMI, modified Medical Research Council score and %forced vital capacity. Prognosis of AE-IIP with possible UIP HRCT pattern was significantly worse than that of AE-IPF.Although AE occurred significantly less frequently in IIP with possible UIP and inconsistent with UIP HRCT patterns than in IPF, the prognosis of AE-IIP with possible UIP HRCT patterns might be worse than that of AE-IPF.
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