Idiopathic Pulmonary Fibrosis is Associated with Circulating Antiepithelial Antibodies

Purpose

Idiopathic pulmonary fibrosis (IPF) is a restrictive fibrotic lung disease of uncertain etiology. Alveolar epithelial injury may be one of the inciting triggers in the pathogenesis of this disorder. We hypothesized that circulating antibodies to alveolar epithelial and endothelial cells may be involved in the pathogenesis of IPF.

Methods

Antibodies to alveolar epithelial and endothelial cells were analyzed by indirect immunofluorescence using alveolar epithelial cells (A549) and human umbilical vein endothelial cells respectively. IgG and IgM antibodies in patients’ serum were evaluated. Patterns of immunofluorescence, including membranous, cytoplasmic, and nuclear staining, were analyzed by fluorescence microscopy. The severity of immunofluorescence was divided into mild, moderate, and severe categories. Fifty-six patients (IPF?=?28, non-IPF ILD?=?9, non-ILD control?=?19) were evaluated for antiepithelial antibodies, and 28 patients (IPF?=?12, non-IPF ILD?=?3, non-ILD control?=?13) were studied for antiendothelial antibodies.

Results

Compared with control subjects, serum from IPF patients displayed significantly higher IgG binding to alveolar epithelial cells (P?=?0.041) with a membranous pattern of immunofluorescence. However, there was no significant difference in immunofluorescence with IgG on endothelial cells (P?=?0.165). In terms of IgM antibodies, there was no differential fluorescence observed for either epithelial or endothelial cells.

Conclusions

There is evidence of increased IgG antibodies directed against alveolar epithelium in IPF. These antibodies may play a significant role in the pathogenesis of this fibrotic disorder. The findings of this study suggest further evaluation of the role of immune mediated alveolar epithelial injury in IPF.     

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive, and usually fatal pulmonary disease for which there are no proven drug therapies. Anti-inflammatory and immunosuppressive agents have been largely ineffective. The precise relationship of IPF to other idiopathic interstitial pneumonias (IIPs) is not known, despite the observation that different histopathologic patterns of IIP may coexist in the same patient. We propose that these different histopathologic 'reaction' patterns may be determined by complex interactions between host and environmental factors that alter the local alveolar milieu. Recent paradigms in IPF pathogenesis have focused on dysregulated epithelial-mesenchymal interactions, an imbalance in T(H)1/T(H)2 cytokine profile and potential roles for aberrant angiogenesis. In this review, we discuss these evolving concepts in disease pathogenesis and emerging therapies designed to target pro-fibrogenic pathways in IPF.     

Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic condition of unknown etiology with an unfavorable outcome from progressively deteriorating respiratory function, leading ultimately to death from respiratory failure. It is characterized by sequential acute lung injury resulting in progressive fixed tissue fibrosis, architectural distortion and loss of function. An excess of profibrotic cytokines and/or a deficiency in antifibrotic cytokines have been implicated in the pathological process as has excessive oxidation. IPF is distinguished from other forms of diffuse pulmonary fibrosis by the presence of the specific histological pattern of usual interstitial pneumonitis.Oral corticosteroids are the usual treatment, but objective response rates are poor and good quality studies do not exist. Other therapies either alone or in combination with corticosteroids are widely used, including azathioprine, colchicine, cyclophosphamide and penicillamine. There is a paucity of good quality information regarding the effectiveness of most noncorticosteroid immunosuppressive agents. Older studies of lesser methodological quality have shown benefits from these drugs, generally when added to corticosteroids. Many were retrospective reviews or uncontrolled, nonrandomized, open-label, prospective studies and often included other histological patterns of disease which are now thought to respond better to immunosuppressive agents. The results of intervention with colchicine and azathioprine have been disappointing when assessed by good quality trials using modern diagnostic criteria. Modern high quality studies are lacking for several agents, notably cyclophosphamide and penicillamine. The older agents may yet prove to be effective but further good quality trials will be necessary to assess these agents adequately.Other new anti-inflammatory, antioxidant, antifibrotic or anticytokine compounds are largely untried or unreported. One trial using interferon-γ-1b showed a significant improvement in pulmonary function but there are concerns regarding the generalizability of this study. Pirfenidone, cyclosporine and acetylcysteine may also prove to be of benefit but current studies are of insufficient quality to allow for any conclusions to be drawn.Currently there is no good evidence to support the routine use of oral corticosteroids, azathioprine, cyclophosphamide, penicillamine, colchicine, cyclosporine or any other immunosuppressive, antifibrotic or immunomodulatory agent in the management of IPF. Interferon, pirfenidone and other new agents may be of benefit but further studies are required. Any recommendations for treatment must therefore be made on an individual and empiric basis. As some other forms of pulmonary fibrosis may respond better to immunosuppressive agents, it remains important to make an accurate diagnosis, by open lung biopsy if necessary.     

New Approaches to Modulating Idiopathic Pulmonary Fibrosis

Until recently, idiopathic pulmonary fibrosis (IPF) has been a devastating and generally fatal disease with no effective therapeutic. New developments in understanding the biology of the disease include a growing consensus that the lesions are mainly composed of cells that originated from resident fibroblasts. New developments in therapeutics include recommendations against several treatment regimes that have been previously used. On a positive note, the orally available drug pirfenidone has been approved for use in IPF in China, Japan, India, and the European Union, but not yet in the United States. Other possibilities for managing IPF include managing gastrointestinal reflux, and limiting excessive salt intake. A variety of potential therapeutics for IPF are in clinical trials; for instance, in a Phase 1b trial, intravenous injections of a recombinant version of the normal human serum protein Serum Amyloid P (SAP, also known as PTX2) improved lung function in IPF patients.     

Blood Biomarkers in Idiopathic Pulmonary Fibrosis

Purpose

Idiopathic pulmonary fibrosis (IPF) is a progressive and lethal lung disease of unknown origin whose incidence has been increasing over the latest decade partly as a consequence of population ageing. New anti-fibrotic therapy including pirfenidone and nintedanib have now proven efficacy in slowing down the disease. Nevertheless, diagnosis and follow-up of IPF remain challenging.

Methods

This review examines the recent literature on potentially useful blood molecular and cellular biomarkers in IPF. Most of the proposed biomarkers belong to chemokines (IL-8, CCL18), proteases (MMP-1 and MMP-7), and growth factors (IGBPs) families. Circulating T cells and fibrocytes have also gained recent interest in that respect. Up to now, though several interesting candidates are profiling there has not been a single biomarker, which proved to be specific of the disease and predictive of the evolution (decline of pulmonary function test values, risk of acute exacerbation or mortality).

Conclusion

Large scale multicentric studies are eagerly needed to confirm the utility of these biomarkers.

     

Genetics of Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is the most common form of interstitial lung disease. IPF is a complex disease, with environmental and genetic factors variably contributing to disease susceptibility and outcomes. A host of common gene variants with modest effect size impart disease risk in patients with sporadic IPF, while rare variants with large effect size influence disease risk in those with familial interstitial pneumonia. In this review, we highlight several common and rare variants underpinning IPF risk and call attention to recently published studies informing our understanding of this risk.     

Evaluation and management of Idiopathic Pulmonary Fibrosis

Idiopathic Pulmonary Fibrosis (IPF) is a most common progressive interstitial lung disease (ILD) of unknown etiology, although majority of patients are elderly male smokers. The main pathogenesis is aberrant recovery of epithelial injury and collagen deposition. Fibrotic nonspecific interstitial pneumonia, connective tissue disease (CTD) especially rheumatoid arthritis (RA) associated ILD, and chronic hypersensitivity pneumonia(CHP) are important differential diagnosis. Main symptoms are non-productive cough and progressive exertional dyspnea. Crucial physical findings are scalene muscle hypertrophy, bibasilar fine crackles, and finger clubbing. The serum markers such as lactate dehydrogenase (LDH) and Krebs von den Lungen-6 (KL-6) are sensitive for ILD detection and activity. Both pulmonary function test (PFT) and the 6-minute walk test (6MWT) are useful tool for evaluation of disease progression of IPF. Serial changes of forced vital capacity (FVC) and 6MWT distance predict mortality in IPF effectively. Recently published international IPF guidelines highlight the importance of chest high resolution computed tomography (HRCT) findings such as honeycombing, traction bronchiectasis (TBE), and sub-pleural reticular opacity. IPF is chronic and progressive; therefore, tracking disease behavior is crucial. Unifying clinical, physiological, and imaging information over time is useful. With regard to its management, two anti-fibrotic drugs such as pirfenidone and nintedanib have been available. These drugs can slow the decline of FVC and prevent acute exacerbation (AE). In this review, I outline the clinical characteristics of IPF, physiological, imaging, pathological findings and review diagnosis process and management.     

The Aging Lung and Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is one of many clinical syndromes that are associated with aging, and is increasing in both incidence and prevalence with the rapid rise in aging populations world-wide. There is accumulating data on how the biology of aging may influence the susceptibility to lung fibrosis in the elderly. In this review, we explore some of the known “hallmarks of aging,” including telomere attrition, genomic instability, epigenetic alterations, loss of proteostasis, cellular senescence and mitochondrial dysfunction in the pathobiology of IPF. Additionally, we discuss age-associated alterations in extracellular matrix that may contribute to the development and/or progression of IPF.     

Current and Future Idiopathic Pulmonary Fibrosis Therapy

The last years have led to advances in the therapeutic management of idiopathic pulmonary fibrosis (IPF), mainly through the discovery of new pathological pathways and drugs and better design of clinical trials. The objective of this review is both to describe the current therapies approved for the treatment of IPF and the emerging therapeutic approaches. Currently, nintedanib and pirfenidone are the basis of IPF therapy, based on the results of large randomized clinical trials showing their safety and efficacy in reducing disease progression. Nonetheless, the ideal IPF therapy is still lacking and trials are underway to test new therapeutic targets. The near future could bring to clinicians and patients a combined therapeutic strategy, hitting the disease from several simultaneous pathways and hopefully leading to clinical stabilization or improvement.     

Sildenafil Therapy and Exercise Tolerance in Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a form of idiopathic interstitial pneumonia characterized by temporally and spatially heterogeneous fibroblast proliferation and poor prognosis. No therapies have been shown in randomized clinical trials (RCT) to influence survival. Twenty-nine subjects were assigned randomly in a pilot study to a double-blind, placebo-controlled, RCT to test sildenafil in patients with IPF with forced vital capacity 40–90% and diffusing capacity 30–90% of predicted. During the 6-month experimental treatment period, patients underwent 6-min walk tests and estimation of dyspnea using the Borg scale at baseline (0 months), 3 months, and 6 months. Participants had moderate impairment of pulmonary function, and there were no significant differences between placebo (n = 15) and sildenafil (n = 14)-treated groups. Sildenafil did not significantly increase 6-min walk test distance (mean distance ± SD after 6-month protocol: placebo 355 ± 82 m, sildenafil 324 ± 41 m; p = 0.256) nor did it lessen dyspnea after exercise (mean Borg score after 6-month protocol: placebo 3.4 ± 1.6, sildenafil 4.1 ± 2.3; p = 0.492). Adverse reactions were few and minor in nature. In this trial, sildenafil did not significantly increase 6-min walk test distance or decrease the Borg dyspnea index in patients with clinically typical IPF. This trial was registered at clinicaltrials.gov as NCT00359736.     

Heterogeneous Remodeling of Lung Vessels in Idiopathic Pulmonary Fibrosis

Recently, several reports suggest differences in the vascularization of the various histopathologic patterns of parenchymal remodeling seen in usual interstitial pneumonia (UIP). In this study, we sought to validate the importance of vascular remodeling in patients with idiopathic pulmonary fibrosis (IPF) and to examine the relationship between vascular remodeling and parenchymal remodeling or pulmonary function. Open lung biopsies were performed in 57 patients with IPF, and vascular changes in alternating areas of parenchymal remodeling (UIP histologic patterns) were studied. Quantitative analysis of the internal area, internal perimeter, wall thickness, and surrounding cellularity of medium or large pulmonary arteries, as well as their distribution according to air/parenchymal ratios, was performed. Semiquantitative analysis also was used to determine the grade of vascular occlusion. An inverse association was found between vascularization and UIP parenchymal remodeling (p < 0.05); that is, the decreased internal luminal area and perimeter as well as the increased wall thickness run in parallel with progression from alveolar collapse toward severe mural-organizing fibrosis with honeycombing. Vascular regression (diminished internal area and perimeter of vessels) was also associated with higher FEV₁, FVC, and RV values (r = 0.48, p< 0.05), reflecting a tight relationship between vascular remodeling and pulmonary function. A progressive regression of vascularization, reflected by different degrees of luminal occlusion after vascular remodeling, coincided with parenchymal remodeling (alveolar collapse, mural-organizing fibrosis, and honeycombing). This vascular regression may be responsible for the impaired wound healing and progressive fibroproliferation found in patients with IPF. Further studies are needed to determine whether this relationship is causal or consequential.     

Sleep-Related Breathing Disorders in Patients with Idiopathic Pulmonary Fibrosis

Idiopathic pulmonary fibrosis (IPF) is a chronic and usually fatal lung disease of unknown etiology. The aim of this study was to describe clinical and polysomnographic features of sleep-related breathing disorders (SRBD) and to identify predictors of obstructive sleep apnea (OSA) in IPF patients. Eight hundred fifty-seven patients with IPF were admitted to the Cleveland Clinic from 2001 to 2005. An all-night polysomnogram (PSG) was performed in 18 of them to investigate complaints suggestive of sleep-disordered breathing. OSA was confirmed in 11 of the 18 IPF patients with complaints suggestive of sleep apnea, while the remain 7 patients had a diagnosis of primary snoring or upper airway resistance syndrome (UARS). All patients showed a reduction in sleep efficiency, REM sleep, and slow wave sleep. The apnea-hypopnea index (AHI) was positively correlated with body mass index (p < 0.0001, r = 0.80). The REM AHI and overall AHI were negatively correlated with FEV₁ (p = 0.008, r = −0.59 and p = 0.04, r = −0.49, respectively) and FVC percentages (p = 0.03, r = −0.50 and p = 0.08, r = −0.42, respectively). Our study is the first describing SRBD in IPF patients. An increased BMI and a significant impairment in pulmonary function testing may be predictors of OSA in this population. In the absence of effective treatments for IPF, the diagnosis and treatment of comorbid SRBD may lead to improvements in quality of life.     

Idiopathic Pulmonary Fibrosis: Epidemiology,Diagnosis andOutcomes

The incidence and prevalence of idiopathic pulmonary fibrosis (IPF) is increasing worldwide. This, combined with its poor prognosis and unpredictable natural history, has amplified the importance of an accurate diagnosis and monitoring. A diagnosis of exclusion, IPF requires a comprehensive clinical evaluation. This results in a clinical context that provides the backdrop for interpretation of the chest imaging and histopathology. A confident or probable usual interstitial pneumonia chest imaging pattern on high-resolution computerized tomography may be diagnostic in the correct clinical context. Outcomes for IPF are unpredictable, ranging from rapid progression with death within months to prolonged stability. Disease activity is monitored by clinical and physiology measures with a declining forced vital capacity, a recognized measure of progression. The available treatments, pirfenidone and nintedanib, are effective at reducing the expected decline in forced vital capacity.