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PubMed1996

Pathogenic mechanisms in the development of diffuse pulmonary fibrosis.

Diffuse pulmonary fibrosis is characterized by abnormal proliferation of mesenchymal cells, specifically fibroblasts and myofibroblasts, and by the accumulation of excessive amounts of matrix proteins, mainly collagens. The development of this pathological process is preceded by an inflammatory response, often dominated by macrophages and lymphocytes, which is mediated by the local release of chemoattractant factors, acting coordinately with an upregulation of cell-surface adhesion molecules. A subsequent persisting fibroproliferative reaction, in both interstitial and intraalveolar spaces, with progressive collagen accumulation distorts the lung architecture irreversibly. Excessive collagen deposition is the result of an imbalance in the collagen turnover rates characterized by a transient increase in collagen synthesis and a decrease in collagen degradation. Fibrosis is considered otherwise to be the final common pathway of a variety of lung disorders, and in this context, the diagnosis of pulmonary fibrosis implies the recognition of an advanced stage in the evolution of a complex process of abnormal repair.

Cell Division↗

PubMed1993

Idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis kills half of its victims within five years of diagnosis. Currently available treatment regimens are disappointing, and the incidence of the disease appears to be increasing. Newer techniques of imaging coupled with laboratory advances in molecular and cellular biology may produce new strategies for modulating the disease process. This article explores new approaches to the diagnosis and management of idiopathic pulmonary fibrosis.

Diagnostic Imaging↗

PubMed2006

High-resolution computed tomography of interstitial pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF), also referred to as cryptogenic fibrosing alveolitis (CFA), is the clinical-radiological-pathological syndrome associated with the most common form of fibrosing interstitial pneumonia, usual interstitial pneumonia (UIP). Unfortunately, the diagnosis of IPF carries with it a relatively poor prognosis. The characteristic features on high-resolution computed tomography (HRCT), consisting of reticular abnormality and honeycombing with basal and peripheral predominance, are virtually diagnostic within the correct clinical context. The extent of fibrosis on HRCT is an important prognostic indicator. When ground-glass attenuation is seen in patients with IPF, it commonly progresses to fibrosis and honeycombing. Complications of IPF include accelerated progression and deterioration, lung cancer, spontaneous air leak, and secondary infection. This article discusses the key imaging features as correlated with histopathology, differential diagnosis, complications, and follow-up evaluation of idiopathic pulmonary fibrosis.

Diagnosis, Differential↗

PubMed1998

Increased prevalence of gastroesophageal reflux in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease (ILD) of unknown etiology. Introduction of acid into the respiratory tree can produce pulmonary fibrosis. Gastroesophageal reflux (GER) has previously been associated with several other respiratory conditions, including pneumonia, bronchitis, and asthma. To investigate prospectively the possible association of GER and IPF, 17 consecutive patients with biopsy-proven IPF and eight control patients with ILD other than IPF underwent dual-channel, ambulatory esophageal pH monitoring. Sixteen of 17 patients with IPF had abnormal distal and/or proximal esophageal acid exposure compared with four of eight control patients (p = 0.02). In the patients with IPF, mean percent distal total (13.6 versus 3.34, p = 0.006), distal upright (12.4 versus 5.1, p = 0.04), distal supine (14.7 versus 0.88, p = 0.02), and proximal supine (7.48 versus 0.24, p = 0.04) esophageal acid exposure times were significantly greater than those in control patients. Only four patients with IPF (25%) with increased acid exposure had typical reflux symptoms such as heartburn or regurgitation. Patients with IPF have a high prevalence of increased esophageal acid exposure, usually without typical GER symptoms. GER in these patients tends to occur at night and extend into the proximal esophagus. Acid reflux may be a contributing factor in the pathogenesis of IPF.

Adult↗

PubMed2001

Analysis of tumor necrosis factor-alpha, lymphotoxin-alpha, tumor necrosis factor receptor II, and interleukin-6 polymorphisms in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is characterized by chronic inflammation that is associated with structural damage of the lung and fibrosis. Although the etiology of IPF is unknown, it is likely to involve an interaction between environmental and multiple genetic components. Animal models of pulmonary fibrosis have shown that proinflammatory mediators are critical at both the inflammatory and fibrotic stages of the disease. Genetic variants exist in genes encoding proinflammatory mediators, as well as in genes encoding their receptors, which makes these genes candidates for the pathogenesis of IPF. In the present study, we examined 12 biallelic polymorphisms in the genes for tumor necrosis factor (TNF)-alpha (+488[G/A], -238[G/A], -308[G/A]), lymphotoxin (LT)-alpha (+720[C/A], +365[C/G], and +249[A/G], determining haplotypes LT-alpha1 to LT-alpha4), tumor necrosis factor-receptor 2 (TNF-RII) (gb:M32315: 676[T/G], 1663[A/G], 1668[T/G], 1690[C/T]), and interleukin- (IL)-6 (promoter -174[G/C], intron 4[A/G]). We also examined the haplotypes determined by the three biallelic polymorphisms in each of the TNF-alpha and LT-alpha genes. As compared with a normal control population, the IPF group showed no significant deviations in genotype, allele, or haplotype frequencies. Surprisingly, in the IPF population, but not in the control population, an increased frequency of cocarriage of the IL-6 intron 4G and the TNF-RII 1690C alleles was observed, despite the location of the two genes on different chromosomes. Moreover, using impairment of carbon monoxide transfer (DL(CO)) adjusted for duration of dyspnea as a marker of rapidity of disease progression, we found that the IL-6 intron 4GG genotype was the only genotype independently associated with lower DL(CO) levels. These findings, if independently confirmed, will be the first to suggest that disease progression in IPF may be linked to a particular genetic marker or to functional polymorphisms in other genes near that marker.

Antigens, CD↗

PubMed2002

[Hepatitis C virus and pulmonary fibrosis].

Idiopathic pulmonary fibrosis (IPF) is a chronic inflammatory interstitial lung disease characterized by an accumulation of alveolar macrophages and neutrophils in the lower respiratory tract, parenchymal injury, and interstitial fibrosis. Although the etiology of IPF is unknown, it has been suggested that viral agents, among which hepatitis C virus (HCV), may be involved in inducing the disease. In patients with chronic hepatitis HCV+ and in those with mixed cryoglobulinemia HCV-associated, HCV may trigger a subclinical lymphocyte alveolitis. Furthermore, pulmonary fibrosis associated with a variety of rheumatic disorders has been reported in 8/300 patients with active chronic hepatitis HCV+. Bronchoalveolar lavage, carried out in 4/8 patients, showed an increased percentage of neutrophils in all of them and a mild increase of lymphocytes in 2 patients. Thoracoscopic lung biopsy was carried out in 2 patients and showed a desquamative interstitial pneumonia; in one case HCV-RNA was found in the pulmonary parenchyma. Although the above observations seem indicate a role for HCV in IFP, further studies are required to define its true importance in the etiopathogenesis of the interstitial lung disease.

Hepatitis C, Chronic↗

PubMed2006

Pathogenetic pathways and novel pharmacotherapeutic targets in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a poorly understood disease that usually leads to death within 5 years of diagnosis. Despite our better understanding of IPF pathogenesis, the etiology and the precise cellular and molecular mechanisms involved are not well known. Current therapies are of unproven benefit. The aim of this review is to identify possible candidate pathways that might offer novel therapeutic targets changing the natural course of this disease. Current therapeutic approaches target at apoptosis, epithelial replacement, fibroblasts/myofibroblasts, procoagulant activity, growth factors production, angiogenesis, Th1 and Th2 cytokines and oxidative stress. Increased epithelial cells apoptosis can contribute to fibrosis, while on the other hand, decreased fibroblast or myofibroblast apoptosis promotes fibrosis. Recent findings support the notion that therapy directed at either inhibition of angiogenic or augmentation of angiostatic CXC chemokines may be a novel approach in the treatment of IPF. Additionally, there is little doubt that the development of novel therapeutic strategies for pulmonary fibrosis should target some profibrotic growth factors and key type II cytokines, such as inteleukin-13. Importantly, persistent activation of intra-alveolar procoagulant activity and subsequent abnormal fibrin turnover enhances a fibrotic response. Furthermore, increased procoagulant activity may interfere with fibrin accumulation and lack of activation of some matrix metalloproteinases responsible for an imbalance in matrix turnover. Finally, oxidative stress with increased production of oxidants in IPF is an additional mechanism proposed to explain epithelial cell apoptosis in this disease. The challenge of future targets for therapeutic intervention is to reconcile different pathogenetic pathways, and we strongly suspect that no single approach will be sufficient for a lethal disease with few therapeutic options.

Apoptosis↗

PubMed1997

Genetic predisposition of idiopathic pulmonary fibrosis.

The pulmonary parenchyma in interstitial fibrosis responds stereotypically to a variety of insults. The observation that only a small subset of persons exposed to known fibrogenic agents develop fibrosis and the induction of pulmonary fibrosis in genetically susceptible mice support a genetic predisposition. The description of familial idiopathic pulmonary fibrosis is the strongest evidence available supporting this hypothesis. Unfortunately, despite all the recent advances in molecular genetic techniques there have been few human studies to date. Given the poor prognosis and the lack of a cure for pulmonary fibrosis, future genetic studies will, it is hoped, clarify the pathogenesis of pulmonary fibrosis and lead to preventive measures and new therapeutic interventions. Idiopathic pulmonary fibrosis typically occurs in patients who are older than 50. The etiology is unknown.

Animals↗

PubMed2006

Evolving concepts of apoptosis in idiopathic pulmonary fibrosis.

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.

Apoptosis↗

PubMed2005

Current and future therapeutic approaches in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a lethal form of idiopathic diffuse lung disorders for which no current treatment is effective. The aim of the present study was to systematically review the current status and novel therapies of IPF, with emphasis on controlled trials. The studies selected included randomised controlled trials using drugs alone and/or in combination for the treatment of adults with IPF and meta-analyses, published in English. Abstracts of identified articles were retrieved and articles possibly fulfilling inclusion criteria were retrieved in full. Two reviewers independently assessed trial quality if there were any included studies. Data quality was based on place of publication and relevance to clinical care. There is a lack of good-quality studies regarding the effectiveness of the most used drugs, including corticosteroids and noncorticosteroid immunosuppressive agents. Oral corticosteroids are the usual treatment. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, cyclophosphamide and colchicine. Interestingly, clinical trials with novel drugs, mainly antifibrotic, anticytokine and immunoregulatory, are currently being investigated in various trial phases. In conclusion, at present, there are no evidence-based therapies for idiopathic pulmonary fibrosis. Further controlled studies are warranted to improve the evidence base for clinical practice.

Clinical Trials as Topic↗

PubMed2006

Chemokine/cytokine cocktail in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and irreversible fibrosing lung disease of unknown etiology and with an unfavorable outcome, leading ultimately to death due to respiratory failure. To date, no treatment strategies have been effective in modifying the natural course of IPF and its fatal outcome. The aberrant parenchymal remodeling is characterized by the expansion of fibroblasts/myofibroblasts, which form characteristic subepithelial foci, and by the abnormal deposition of extracellular matrix in the lung parenchyma. Although the pathophysiology underlying this disease has not yet been fully elucidated, animal models of pulmonary fibrosis have provided contributions in dissecting the molecular basis of this disease, focusing on the role of cytokines and chemokines as important pathogenetic mediators of lung fibrosis. Starting with the data obtained from animal models, this article provides a comment on a number of findings that suggest the possible role of the chemokine/cytokine system in the pathogenesis of IPF.

Animals↗

PubMed1998

Cyclophosphamide pulse therapy in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive disorder with poor prognosis. Response to treatment is infrequent and the use of immunosuppressive agents other than corticosteroids is the subject of ongoing discussion because of uncertain efficacy and side-effects. To determine the efficacy and safety of cyclophosphamide pulse therapy in IPF, this study retrospectively analysed 18 patients with progressive IPF who were treated with intermittent i.v. cyclophosphamide (1-13 g x month(-1)) and additional oral prednisolone for 1 yr. Static lung volumes, arterial oxygen tension (Pa,O2) at rest, clinical symptoms and potential treatment-related side-effects were recorded. Cyclophosphamide had to be stopped in one patient, owing to repeated pulmonary infection; 11 patients were responders (five improving, six stabilizing) and six patients deteriorated. The change in vital capacity (VC) of responders was +6.7+/-18.0% (mean +/-SD), compared with -20.6+/-18.2% in nonresponders (p=0.008). Pa,O2 remained constant in responders (+0.13+/-0.88 kPa (+1.0+/-6.6 mmHg)), while it decreased in nonresponders (-2.08+/-1.92 kPa (-15.6+/-14.4 mmHg, p=0.008)). Additional prednisolone was reduced by 19.1+/-13.4 mg in responders, compared with 6.7+/-16.3 mg in nonresponders (p=0.02). VC at initiation of therapy was higher in responders (60.2+/-10.2 versus 40.3+/-12.9% predicted; p=0.004). No side-effects occurred, other than respiratory tract infection. These data demonstrate that intravenous cyclophosphamide pulse therapy may be a favourable regimen for certain patients with progressive idiopathic pulmonary fibrosis. Patients with a vital capacity of more than 50% predicted and a shorter duration of disease may benefit most.

Administration, Oral↗

PubMed1996

Immunology of idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an immunomediated disorder characterized by a chronic inflammation of the lower respiratory tract, type I epithelial cell damage, accumulation of connective tissue components, fibroblast proliferation, and deposition of matrix proteins. The past few years have seen remarkable advances in the understanding of the immunopathogenesis of IPF. It is becoming clear that, although normal inflammatory reaction in the lung generally resolves, the rapidity and efficiency with which inflammatory constituents are removed from alveolar airspaces is altered in patients with IPF. The loss of the balance between events that mediate resolution or perpetuation of inflammatory responses sets the stage for severe lung injury, tissue remodelling, and the irreversible development of pulmonary fibrosis. This review outlines the complexity of cellular signalling processes taking place in fibrotic lung, providing a bridge between basic research and clinical relevance in the treatment of these patients.

Cell Communication↗

PubMed2003

Complement receptor 1 gene polymorphisms are associated with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic, fibrotic disorder underlain by aberrant wound healing of repeated lung injury. Environmental triggers and genetic background are likely to act as modifiers of the fibrotic response. Erythrocyte complement receptor 1 is a membrane protein mediating the transport of immune complexes to phagocytes. Three gene polymorphisms are related to the erythrocyte surface density of complement receptor 1 molecules, which in turn are related to the rate of immune complexes' clearance. There is evidence of association between sarcoidosis and the complement receptor 1 gene. We wondered whether IPF is associated with the complement receptor 1 gene alleles coding for a reduced molecule/erythrocyte ratio. We studied 74 patients and 166 control subjects. Three polymorphic sites of the gene, A3650G exon 22, HindIII RFLP intron 27, and C5507G exon 33, were analyzed and found to be in linkage disequilibrium. The GG genotype for the C5507G exon 33 polymorphism was significantly more common in patients with IPF than in control subjects (odds ratio = 6.232, 95% confidence interval = 2.198-18.419, p = 0.00023). The significant difference was found in both sexes. These findings agree with speculations on the role of the complement receptor 1 gene in idiopathic pulmonary fibrosis.

Aged↗

PubMed2006

Long-term clinical effects of interferon gamma-1b and colchicine in idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF)/usual interstitial pneumonia is a deadly disease with no effective treatment. The purpose of this randomised prospective multicentric study was to characterise the clinical effects of interferon gamma (IFN-gamma) 1b administered subcutaneously thrice weekly versus colchicine for 2 yrs. This study had no pre-specified end-points. Fifty consecutive IPF patients were randomised. Patients with mild-to-moderate IPF were eligible for the study if they had histologically proven IPF, or, in the absence of surgical biopsy, fulfilled the European Respiratory Society/American Thoracic Society criteria. In the intent-to-treat population, five out of 32 (15.6%) IFN-gamma-1b patients and seven out of 18 (38.8%) colchicine patients died after a median follow-up period of 25 months Patients treated with IFN-gamma 1b showed a better outcome after 2 yrs of therapy, and fewer symptoms, as assessed using the St George's Respiratory Questionnaire, after 12 months of therapy. Also, the IFN-gamma-1b group exhibited a higher forced vital capacity (percentage of the predicted value) after 24 months of treatment. No significant differences were detected in resting arterial oxygen tension, total lung capacity (% pred), transfer factor of the lung for carbon monoxide (% pred) and high-resolution computed tomographic scoring between the two treatment groups. These data suggest that long-term treatment with interferon gamma 1b may improve survival and outcome in patients with mild-to-moderate idiopathic pulmonary fibrosis. Further studies are needed to verify these results.

Adult↗

PubMed2001

Lung cancer in patients with idiopathic pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) was reported to be associated with increased risk of lung cancer as a result of the occurrence of atypical or dysplastic epithelial changes in fibrosis which progressed to invasive malignancy. In that situation, the cancer will develop in the area of major fibrosis. To investigate the direct relationship between fibrosis and cancer development, the real concordance rate of the two lesions in the chest computed tomography (CT) was analysed and compared to the histological types of lung cancer. The subjects included 63 patients with combined lung cancer and IPF (IPF-CA), 218 patients with lone IPF, and 2,660 patients with primary lung cancer. All patients were diagnosed at Asan Medical Center during the same period. The age, percentage of smokers, and the male sex were significantly higher in IPF-CA compared with lone IPF. The odds ratio of smoking was 2.71 compared to nonsmoking IPF controls. In IPF-CA, 56% of the cancer was located in the periphery of the lung and 52% in the upper lobe. The majority of the cancers (64%) were found in the nonfibrotic area at chest CT. The most frequent cell type was squamous cell carcinoma (35%), and there was no significant difference in the cancer cell type between IPF-CA and total lung cancer population. These findings suggest that in combined lung cancer and idiopathic pulmonary fibrosis patients, the features of the lung cancer are similar to the total lung cancer population.

Aged↗

PubMed2005

Pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease limited to the lungs and associated with the histologic appearance of usual interstitial pneumonia (UIP) on surgical lung biopsy. The estimated prevalence in the United States is between 35,000 and 55,000 cases,and evidence suggests that the prevalence is increasing for IPF. Risk factors associated with pulmonary fibrosis include smoking, environmental exposures, gastroesophageal reflux dis-ease, commonly prescribed drugs, diabetes mellitus, infectious agents, and genetic factors. The diagnosis requires a careful history and physical examination, characteristic physiological and radiological studies, and, in some cases, a surgical lung biopsy. The natural history of IPF is not known, but evidence supports the concept of a continuum of idiopathic interstitial pneumonias that may overlap in time. Most patients with IPF succumb to respiratory failure, cardiovascular disease, lung cancer, pulmonary embolism, infection, and other health problems. The median survival time for patients with IPF is less than 3 yr. Factors that predict poor outcome include older age, male gender, severe dyspnea, history of cigarette smoking, severe loss of lung function, appearance and severity of fibrosis on radiological studies, lack of response to therapy,and prominent fibroblastic foci on histopathologic evaluation. Conventional therapy (corticosteroids, azathioprine, cyclophosphamide) provides only marginal benefit. Lung transplantation should be considered for patients with IPF refractory to medical therapy. In light of the poor prognosis and lack of response to available anti-inflammatory therapy, alternative approaches to therapy are being pursued. Emerging strategies to treat patients with IPF include agents that inhibit epithelial injury or enhance repair, anti-cytokine approaches, agents that inhibit fibroblast proliferation or induce fibroblast apoptosis, and other novel approaches.

Adult↗

PubMed2005

Evaluation of health-related quality-of-life and dyspnea scales in patients with idiopathic pulmonary fibrosis. Correlation with pulmonary function tests.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) has a profound impact on the functional status of patients. We sought to determine whether the health-related quality of life is affected in patients with IPF. METHODS: A total of 25 patients with IPF (aged 41-72 years) and 30 healthy subjects were evaluated in a cross-sectional study. All subjects were asked to complete three dyspnea scales-the Borg (BORG), the oxygen-cost diagram (OCD) and the modified MRC questionnaire-as well as a number of health-related quality-of-life (HRQoL) questionnaires, i.e., the Saint-George Respiratory Questionnaire (SGRQ), the Quality of Well-Being (QWB) and the Hospital Anxiety and Depression Questionnaire (HAD). Pulmonary function tests, arterial blood gas measurements at rest and during exercise, chest radiographs and the duration of disease were used for correlation. RESULTS: The mean total values of all of the scales used were near the lower best values of each scale in IPF patients and were significantly different from values in the control group. Lung volumes (FVC and TLC) correlated significantly with the SGRQ. All dyspnea scales (BORG, OCD and MRC) showed a significant correlation with diffusing capacity and blood oxygenation at rest and during exercise. The duration of the disease correlated with all dyspnea scales used and with the SGRQ and HAD Questionnaires. CONCLUSIONS: Our results suggest that dyspnea scales and the SGRQ are sensitive tools for assessing health-related quality of life in patients with IPF.

Journal Article↗