Abnormal vascular phenotypes in patients with idiopathic pulmonary fibrosis and secondary pulmonary hypertension.
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Gene Expression↗
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Results for “PULMONARY FIBROSIS”
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[Markers of thrombophilia in pulmonary fibrosis complicated by pulmonary hypertension].
AIM: To determine the role of enhanced blood coagulation in pathogenesis of pulmonary hypertension (PH) at an early stage of fibrosing alveolitis (FA). MATERIAL AND METHODS: Clinical, functional, roentgenological, coagulation and immunological examinations were performed in 17 patients with idiopathic FA (IFA), in 6 patients with exogenic allergic alveolitis (EAA), in 15 FA patients with diffuse diseases of the connective tissue (FA-DDCT). The diagnosis was verified with high resolution computed tomography (HRCT). Lesser circulation was assessed by Doppler echocardiography. Morphological impairment of the lungs was specified in all the patients using analysis of the bronchoalveolar lavage. In 9 FA patients the diagnosis was verified at thoracoscopic biopsy of the lung. The control group consisted of 16 healthy volunteers. Thrombin-antithrombin complex (TAT) and thrombocytic factor 4 (TF-4) were estimated with ELISA as stable, highly sensitive markers of thrombophilia. RESULTS: The TF-4 level was elevated in all IPD patients (p < 0.05), the elevation being highest in FA-DDCT (p < 0.007). With FA progression, TF-4 concentration went down. A weak negative correlation (p < 0.047, r = -0.38) was found with average pressure in the pulmonary artery (PAAP). TAT was higher than control in all the groups (p < 0.05). Maximal TAT values were registered in EAA. If HRCT detected active inflammation and in development of irreversible fibrous changes TAT was higher vs control. A direct correlation between TAT level and PAAP was not found. CONCLUSION: Disorders in thrombocytic and plasmic links of hemostasis are detectable early in IPD. Stable markers of thrombophilia (TAT and TF-4) reflect activity of inflammation in FA. They can be also used as sensitive diagnostic tests for diagnosis of PH and diagnosis of patients with activated coagulation system in IPD.
Adult↗
[Idiopathic pulmonary fibrosis: correlation between helical CT findings and pulmonary function test results].
OBJECTIVE: To determine the correlation between helical CT findings and pulmonary function test (PFT) results from patients with idiopathic pulmonary fibrosis(IPF). METHODS: Helical CT scan was performed in 32 cases with clinically and/or pathologically proved idiopathic pulmonary fibrosis. Pulmonary function test for each patient was performed within 5 days before or after CT scan. The correlation between CT findings and pulmonary function test results was assessed. RESULTS: Pulmonary function test revealed characteristic restrictive ventilatory defect with reduction of total lung capacity, residual volume, vital capacity, and diffusing capacity of the lung for carbon monoxide. The patients with different severities of pulmonary function impairment had different CT features. 4 of 5 cases with slight impairment of the pulmonary function had the ground-glass opacity, 11 cases with moderate impairment showed the thickened interlobular septa (11/11, 100%), thickened lobular interstitium (9/11, 82%), distorted lobular structures (11/11, 100%) and thickened bronchovascular bundles (10/11, 91%). 16 cases with marked impairment showed the honeycombing (16/16, 100%) and the traction bronchiectasis (9/16, 55%). CONCLUSION: CT can provide significant information for the assessment of the pathologic severity of idiopathic pulmonary fibrosis. There is good correlation between CT findings and pulmonary function test results. CT combined with pulmonary function test can predict the progression, long term survival and response to therapy.
Adult↗
A placebo-controlled trial of interferon gamma-1b in patients with idiopathic pulmonary fibrosis.
BACKGROUND: Idiopathic pulmonary fibrosis is a progressive, fatal disease with no known efficacious therapy. METHODS: In a double-blind, multinational trial, we randomly assigned 330 patients with idiopathic pulmonary fibrosis that was unresponsive to corticosteroid therapy to receive subcutaneous interferon gamma-1b or placebo. RESULTS: Over a median of 58 weeks, interferon gamma-1b therapy did not significantly affect the primary end point of progression-free survival, defined as the time to disease progression or death, and no significant treatment effect was observed on measures of lung function, gas exchange, or the quality of life. Ten percent of patients in the interferon gamma-1b group died, as compared with 17 percent of patients in the placebo group (P=0.08). Treatment with interferon gamma-1b was associated with more frequent constitutional symptoms. However, the rates of treatment adherence and premature discontinuation of treatment were similar in the two groups. More pneumonias were reported among patients in the interferon gamma-1b group, but the incidence of severe or life-threatening respiratory tract infections was similar in the two groups. CONCLUSIONS: In a well-defined population of patients with idiopathic pulmonary fibrosis, interferon gamma-1b did not affect progression-free survival, pulmonary function, or the quality of life. Owing to the size and duration of the trial, a clinically significant survival benefit could not be ruled out.
Disease Progression↗
Simultaneous occurrence of grey platelet syndrome and idiopathic pulmonary fibrosis: a role for abnormal megakaryocytes in the pathogenesis of pulmonary fibrosis?
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Adult↗
Lung and chest wall mechanics in ventilated patients with end stage idiopathic pulmonary fibrosis.
BACKGROUND: Idiopathic pulmonary fibrosis is an inflammatory disease which leads to chronic ventilatory insufficiency and is characterised by a reduction in pulmonary static and dynamic volumes. It has been suggested that lung elastance may also be abnormally increased, particularly in end stage disease, but this has not been systematically tested. The aim of this study was to assess the respiratory mechanics during mechanical ventilation in patients affected by end stage disease. METHODS: Respiratory mechanics were monitored in seven patients with idiopathic pulmonary fibrosis being ventilated for acute respiratory failure (PaO2/FiO2 5.8 (0.3); pH 7. 28 (0.02); PaCO2 8.44 (0.82) kPa; tidal volume 3.4 (0.2) ml/kg; respiratory rate 35.1 (8.8) breaths/min) using an oesophageal balloon and airway occlusion during constant flow inflation. The total respiratory system mechanics (rs) was partitioned into lung (L) and chest wall (w) mechanics to measure static intrinsic positive end expiratory pressure (PEEPi), static (Est) and dynamic (Edyn) elastances, total respiratory resistance (Rrs), interrupter respiratory resistance (Rint,rs), and additional respiratory resistance (DeltaRrs). RESULTS: PEEPi was negligible in all patients. Edyn,rs and Est,rs were markedly increased (60.9 (7.3) and 51.9 (8. 0) cm H2O/l, respectively), and this was due to abnormal lung elastance (dynamic 53.9 (8.0) cm H2O/l, static 46.1 (8.1) cm H2O/l) while chest wall elastance was only slightly increased. Rrs and Rint, rs were also increased above the normal range (16.7 (4.5) and 13.7 (3.5) cm H2O/l/s, respectively). RL and Rint,L contributed 88% and 89%, on average, to the total. Edyn,rs, Est,rs, Rrs and Rint,rs were significantly correlated with the degree of hypercapnia (r = 0.64 (p<0.01), r = 0.54 (p<0.05), r = 0.84 (p<0.001), and r = 0.72 (p<0. 001), respectively). CONCLUSIONS: The elastances and resistances of the respiratory system are significantly altered in ventilated patients with end stage idiopathic pulmonary fibrosis. These features are almost totally due to abnormalities in lung mechanics. These profound alterations in elastic and resistive mechanical properties at this stage of the disease may be responsible for the onset of hypercapnia.
Elasticity↗
[A case of idiopathic pulmonary fibrosis associated with bilateral pulmonary arterial thrombosis found at autopsy].
A 73-year-old woman admitted to the hospital with dyspnea on exertion. Chest radiography revealed a diffuse interstitial shadow; PaO2 was 72 Torr, and PaCO2 was 41 Torr. Laboratory examination results were compatible with idiopathic pulmonary fibrosis (IPF). Prednisolone relieved the dyspnea, but tapering of the drug led to a recurrence of this symptom. Pulse therapy was started and azathioprine was added to the corticosteroid. Over the course of 6 months of treatment, the patient's respiratory function remained fairly stable. Then respiratory distress was induced by an attack of atrial fibrillation, with relief provided by anti-arrhythmic drugs and large doses of corticosteroids. The patient died suddenly 3 weeks later. An autopsy revealed large thrombi in both pulmonary arteries with 90% stenosis. Parts of the thrombi were organized, which suggests that 2-3 weeks had elapsed since initial thrombus formation. Histological examination of lung tissue showed usual interstitial pneumonia. Pulmonary thromboembolism should be considered in patients with IPF if respiratory distress suddenly and unexpectedly worsens.
Aged↗
Functional predictors of exertional dyspnea, 6-min walking distance and HRCT fibrosis score in idiopathic pulmonary fibrosis.
BACKGROUND: Exertional dyspnea and exercise incapacity are the most prominent and disabling symptoms and the main contributors to health-related quality of life in patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVES: There are no comprehensive studies on pulmonary function tests (PFTs), dyspnea, exercise capacity and radiographic scores in IPF. We therefore sought to investigate the functional variables that can predict dyspnea, exercise capacity and disease extent in IPF. METHODS: Thirty-four patients with IPF according to the ATS/ERS criteria underwent PFTs, Medical Research Council (MRC) dyspnea scoring, 6-min walking distance (6-MWD) and radiographic evaluation of fibrosis (HRCT score). RESULTS: The 6-MWD (% pred.) was more impaired than PFTs. Residual volume (RV) showed the best correlation with the extent of fibrosis (r = -0.67, p = 0.0001) and, together with the alveolar-arterial gradient for O(2) [DeltaP(A - a)O(2)], was an independent predictor of disease extent (R(2) = 0.44). PFTs showed significant though weak correlations with MRC score and 6-MWD. According to the regression analysis, DL(CO) and the HRCT fibrosis score were independent predictors of dyspnea, though they explained only 28% of the overall variance. FEV(1) and DeltaP(A - a)O(2) were independent predictors of 6-MWD (R(2) = 0.31). CONCLUSIONS: PFTs and lung volumes in particular are closely related to the HRCT score, a measure of the extent of IPF. The correlation of dyspnea score and 6-MWD to PFTs is limited, due to the complexity of mechanisms leading to exercise limitation in IPF. Therefore dyspnea and exercise performance are largely independent indices and should be followed together with PFTs and HRCT score in order to better assess the status and progress of IPF patients.
Aged↗
Cytokine regulation of pulmonary fibrosis in scleroderma.
Pulmonary fibrosis occurs in up to 70% of scleroderma patients and progresses to cause severe restrictive lung disease in about 15% of patients. The mechanisms that cause pulmonary fibrosis in scleroderma remain incompletely understood. Increased amounts of mRNA or protein for multiple profibrotic cytokines and chemokines have been identified in lung tissue or broncholveolar lavage samples from scleroderma patients, when compared to healthy controls. These cytokines include transforming growth factor (TGF)-beta, connective tissue growth factor (CTGF), platelet-derived growth factor (PDGF), oncostatin M (OSM), monocyte chemotactic factor-1 and pulmonary and activation-regulated chemokine (PARC). Potential cellular sources of these profibrotic cytokines and chemokines in scleroderma lung disease include alternatively activated macrophages, activated CD8+ T cells, eosinophils, mast cells, epithelial cells and fibroblasts themselves. This review summarizes the literature on involvement of cytokines and chemokines in the development of pulmonary fibrosis in scleroderma.
Adult↗
Corticosteroids for idiopathic pulmonary fibrosis.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF), also called cryptogenic fibrosing alveolitis (CFA), is a lethal form of diffuse lung disorder of unknown origin; the mean survival being two to four years. Currently recommended and most prescribed therapy for IPF is based on the use of systemic corticosteroids, even if no formal demonstration of efficacy of this treatment of IPF is available. Furthermore, new insights from pathological studies have produced a new hypothesis, based upon the central role played by aberrant wound healing following repeated lung injury, weakening the rationale basis of the use of corticosteroids in IPF, previously considered simply a chronic inflammatory disease. OBJECTIVES: The objective of the review was to determine the efficacy of corticosteroids in the treatment of adults with IPF. SEARCH STRATEGY: We searched the Cochrane Central Register of Controlled Trials (The Cochrane Library Issue 2, 2002), MEDLINE (January 1966 to May 2002) and EMBASE (January 1985 to December 2002) and reference lists of articles. We searched reference lists of published articles to identify trials. SELECTION CRITERIA: Randomised controlled trials (RCT) and controlled clinical trials (CCT) using corticosteroids alone for the treatment of adults with IPF. DATA COLLECTION AND ANALYSIS: Abstracts of identified articles were retrieved and articles possibly fulfilling inclusion criteria were retrieved in full. Two reviewers would have independently assessed trial quality if there had been any included studies. MAIN RESULTS: Fifteen studies were selected as potentially eligible for meta-analysis. After further analysis of full text papers, no RCTs or CCTs were identified as suitable and therefore no data was available for inclusion in any meta-analysis. All studies were excluded due to inadequate methodologies. REVIEWER'S CONCLUSIONS: At present, there is no evidence for an effect of corticosteroid treatment in patients with Idiopathic pulmonary fibrosis(IPF)/usual interstitial pneumonia (UIP). Given developments in understanding of the pathogenesis of IPF, randomised controlled trials designed to test the efficacy of corticosteroids will probably never be designed. As other forms of pulmonary fibrosis such as non-specific interstitial pneumonia are reported to show a better response to corticosteroids, it is crucial to make an accurate diagnosis in each patient. Moreover, therapies with immunomodulatory rather than anti-inflammatory or immunosuppressive effects may be more promising for the effective treatment of IPF/UIP.
Adrenal Cortex Hormones↗
A regulatory network underlying idiopathic pulmonary fibrosis.
BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive interstitial lung disease in which genetic susceptibility interacts with epithelial, immune, and mesenchymal remodeling. Although the chromosome 11p15.5 locus contains established IPF susceptibility signals near MUC5B and TOLLIP, the broader regulatory architecture of this region remains incompletely resolved. METHODS: We integrated IPF genome-wide association study summary statistics with methylation, expression, and protein quantitative trait loci using summary-data-based Mendelian randomization (SMR). SMR-prioritized candidates were evaluated in independent transcriptomic and methylation cohorts and further contextualized using microRNA, transcription-factor, protein-interaction, machine-learning, single-cell, and spatial transcriptomic analyses. Fibrosis-associated expression patterns were assessed in a bleomycin-induced pulmonary fibrosis rat model. RESULTS: The analyses recovered the established MUC5B and TOLLIP signals and prioritized BRSK2 as a comparatively underexplored candidate supported by eQTL-based SMR and independent molecular evidence. The BRSK2 pQTL association did not pass the HEIDI test and was therefore not interpreted as convergent protein-level genetic evidence. Network analyses linked BRSK2 to cell-cycle, metabolic-stress, and senescence-related programs, while cross-cohort machine learning prioritized FOXA2, CDC25B, and NFE2 as informative network features. Single-cell and spatial analyses localized BRSK2 preferentially to fibroblast and myofibroblast compartments and to regions with greater histological fibrosis severity. In fibrotic rat lungs, BRSK2 expression increased, whereas FOXA2 and CDC25B decreased at the transcript and protein levels. CONCLUSIONS: These findings refine the molecular landscape of the chromosome 11p15.5 IPF susceptibility locus and prioritize BRSK2 as a candidate component of an IPF-associated profibrotic fibroblast state. Its causal contribution, direct regulatory relationships, and therapeutic tractability require targeted mechanistic validation.
Idiopathic Pulmonary Fibrosis↗
Rat alveolar myofibroblasts acquire alpha-smooth muscle actin expression during bleomycin-induced pulmonary fibrosis.
The majority of fibroblasts in alveolar septa are characterized by the presence of cytoplasmic bundles of microfilaments that contain cytoplasmic actin isoforms; these cells have been named contractile interstitial cells or V-type myofibroblasts. In the rat, they express desmin as intermediate filament protein. In this study, we explored the possibility that modulation and replication of such septal fibroblasts result in the appearance of alpha-smooth muscle (alpha-SM) actin-positive myofibroblasts, typical of lung fibrosis. Experimental pulmonary fibrosis was produced by a unique intratracheal instillation of bleomycin to 28 rats. Eight additional rats used as controls received the equivalent volume of saline. Paraffin and frozen sections of lungs were examined at days 1, 3, 5 and 7 after treatment. Microfilaments and intermediate filaments were stained using antibodies against total actin, alpha-SM actin, desmin, vimentin, keratin, and SM myosin. Electron microscopic labeling of desmin and alpha-SM actin using immunogold technique was done on Lowicryl K4M resin-embedded specimens. alpha-SM actin appeared in desmin-positive alveolar fibroblasts as early as 24 hours after intratracheal bleomycin instillation; the modulation of alpha-SM actin in these cells was preceded by a lymphomonocytic infiltration of alveolar septa. Twenty-four hours to 3 days after bleomycin administration, a proliferation of alveolar myofibroblasts occurred. Fibrosis with laying down of collagen fibers took place after the above mentioned cellular modifications. Our results support the view that septal fibroblastic cells can modulate into typical alpha-SM actin-containing myofibroblasts during experimental bleomycin-induced pulmonary fibrosis. In such a modulation a possible role of cytokines, particularly of transforming growth factor-beta, is considered.
Actin Cytoskeleton↗
Gut microbiota dynamics and metabolic pathways associated with bleomycin-induced pulmonary fibrosis progression.
BACKGROUND: Pulmonary fibrosis (PF) is a progressive respiratory disease characterized by epithelial injury, aberrant repair and excessive extracellular matrix deposition. Although the gut-lung axis is increasingly implicated in respiratory disorders, stage-resolved characterization of gut microbiota taxonomic and functional potential during PF development is limited. METHODS: We established a bleomycin-induced murine PF model and performed cross-sectional shotgun metagenomic sequencing of fecal samples from separate cohorts at three defined stages: baseline (control), day 7 (early fibrosis; M7), and day 14 (established fibrosis; M14). Microbial taxonomy, alpha/beta diversity, and predicted functional capacity were inferred using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Carbohydrate-Active enZymes (CAZy) annotations; associations were assessed using Procrustes and Spearman correlation analyses. RESULTS: Histopathology and immunohistochemistry confirmed progressive fibrogenesis with increased TGF-β1 and α-SMA expression. Compared with baseline, bleomycin-treated groups exhibited stage-specific shifts in gut microbial composition, including depletion of mucin-associated taxa (e.g., Prevotella, Akkermansia muciniphila) and expansion of Muribaculaceae- and Clostridiaceae-affiliated taxa. Alpha and beta diversity metrics differed across groups. KEGG/CAZy-based annotations revealed predicted, stage-dependent changes in microbial metabolic potential, including early reductions in pathways related to amino acid and glycan metabolism (M7) and later increases in predicted starch/sucrose catabolism, phosphotransferase system (PTS) representation, and secondary bile acid biosynthesis (M14). Correlation analyses linked compositional shifts to these predicted functional changes. CONCLUSION: In a stage-resolved, cross-sectional study, bleomycin-associated pulmonary fibrosis was accompanied by compositional and predicted functional alterations in the gut microbiota. These data identify candidate taxa and predicted pathways for follow-up mechanistic testing, but functional (metabolomic) and causality experiments are required to confirm whether and how microbial changes contribute to PF pathogenesis.
Animals↗
The rapamycin analogue SDZ RAD attenuates bleomycin-induced pulmonary fibrosis in rats.
Pulmonary fibrosis is characterized by excessive deposition of extracellular matrix proteins within the pulmonary interstitium. The new macrolide immunosuppressant SDZ RAD, a rapamycin analogue, inhibits growth-factor dependent proliferation of mesenchymal cells and might therefore be of therapeutic interest for the treatment of fibrotic lung disease. In this study the effect of SDZ RAD on lung-collagen accumulation in the bleomycin model of pulmonary fibrosis in rats was investigated. SDZ RAD (2.5 mg x kg(-1) x day(-1)) or drug vehicle were administered orally by daily gavage. Successful dosing was confirmed by measuring splenic weight. Total lung-collagen content was measured by high-performance liquid chromatographic quantitation of hydroxyproline. In animals given bleomycin and drug vehicle, total lung collagen was increased by 182+/-11% (mean+/-SEM) compared with saline controls at 14 days (p<0.001). The increase in lung-collagen accumulation was reduced by 75+/-12% (p<0.01) in animals given SDZ RAD and was accompanied by a concomitant 56+/-6% (p<0.001) reduction in lung weight. SDZ RAD is currently in clinical trials for the prevention of solid organ graft rejection, another condition characterized by excessive extracellular matrix production. The authors propose that SDZ RAD warrants evaluation as a novel therapeutic agent for fibrotic lung disease.
Animals↗
Pulmonary fibrosis.
Diffuse interstitial pulmonary fibrosis is the end result of alveolar damage which may occur as a sudden acute incident or as a slowly developing process. Potentiating factors include release of enzymes and generation of oxygen radicals by granulocytes. Evidence from studies on broncho-alveolar lavage fluid and from immunocytochemistry indicate that an autoimmune process has an important but, as yet, not clearly defined role in initiating the disease. The fibrosis is probably due to proliferation of small clones of fast growing fibroblasts of a specific phenotype. Bronchiolitis obliterans, organizing pneumonia, idiopathic pulmonary fibrosis, usual interstitial pneumonia and desquamative interstitial pneumonia represent different aspects of the same condition. Their varied morphological appearances probably reflect the fact that tissue has been taken at different stages in the development of the disease.
Bronchoalveolar Lavage Fluid↗
[An anatomo-clinical case of diffuse pulmonary fibrosis with chronic sclerodermic pulmonary heart].
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Female↗
Molecular mechanisms of pulmonary fibrosis and current treatment.
Pulmonary fibrosis is a common response to various insults or injuries to the lung. Although there are various initiating factors or causes, the terminal stages are characterized by proliferation and progressive accumulation of connective tissue replacing normal functional parenchyma. The pathogenesis of pulmonary fibrosis includes endothelial and epithelial cell injury, production of inflammatory cells and their mediators, and fibroblast activation. Conventional therapy consisting of glucocorticoids or cytotoxic drugs is usually ineffective in preventing progression of the disease. Further understanding of the molecular mechanisms of endothelial and epithelial cell injury, inflammatory reaction, fibroblast proliferation, collagen deposition and lung repair, should lead to the development of effective treatments against pulmonary fibrosis. Accordingly, this review summarizes recent progress made in understanding the molecular mechanisms of pulmonary fibrosis. A detailed discussion is presented regarding each of the potential new therapies which have emerged from the animal models of pulmonary fibrosis and which have been developed through advances in cellular and molecular biology.
Animals↗
[Diffuse pulmonary ossification associated with idiopathic pulmonary fibrosis].
Diffuse pulmonary ossification is a rare entity that presents with the formation of mature bone in the pulmonary parenchyma and is associated with diffuse and chronic lung disease, heart disease, or other system disorders. Diffuse pulmonary ossification is usually a postmortem finding by the pathologist. In the case we report, the diagnosis was established by open lung biopsy. The patient was a 79-year-old man with dyspnea, dry cough, and weight loss. He had been a smoker. A chest x-ray revealed reticulonodular bilateral pulmonary infiltrates. Computed tomography revealed interstitial disease predominantly in the septum with multiple cavitations that tended to form honeycomb patterns. Pleural thickening, retraction of the parenchyma, and bilateral fibrosis were also visible. A clinical diagnosis of interstitial fibrosis was established and the patient s course was unfavorable. An open lung biopsy was performed. The lung tissue specimens revealed zones with collapsed alveoli and others with emphysema, some of which produced secretion and erythrocytic extravasation. Interstitial vascular congestion was apparent; bronchioles presented mononuclear and some polymorphonuclear inflammatory infiltrates. Noteworthy was the presence of predominantly interstitial, multicentric foci of osseous trabeculae --some of which included adipose bone marrow. Diffuse pulmonary ossification is usually an incidental finding in autopsies of patients with a history of diffuse chronic pulmonary disease, but it is an unusual diagnosis in living patients. Diffuse pulmonary ossification is of no prognostic significance in pulmonary fibrosis. It is a marker of the chronicity and/or severity of the fibrosis.
Aged↗