Idiopathic pulmonary fibrosis: pathobiology of novel approaches to treatment

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of unknown cause that conveys a dismal prognosis. In the United States there are currently no licensed therapies for treatment of IPF. The development of effective IPF clinical trials networks across the United States and Europe, however, has led to key developments in the treatment of IPF. Advances in understanding of the pathogenetic processes involved in the development of pulmonary fibrosis have led to novel therapeutic targets. These developments offer hope that there may, in the near future, be therapeutic options available for treatment of this devastating disease.     

A review of current and novel therapies for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a progressively fibrotic interstitial lung disease that is associated with a median survival of 2-3 years from initial diagnosis. To date, there is no treatment approved for IPF in the United States, and only one pharmacological agent has been approved outside of the United States. Nevertheless, research over the past 10 years has provided us with a wealth of information on its histopathology, diagnostic work-up, and a greater understanding of its pathophysiology. Specifically, IPF is no longer thought to be a predominantly pro-inflammatory disorder. Rather, the fibrosis in IPF is increasingly understood to be the result of a fibroproliferative and aberrant wound healing cascade. The development of therapeutic targets has shifted in accord with this paradigm change. This review highlights the current understanding of IPF, and the recent as well as novel therapeutics being explored in clinical trials for the treatment of this devastating disease.KEY WORDS : Idiopathic pulmonary fibrosis/drug therapy, idiopathic pulmonary fibrosis/pathology, molecular targeted therapy, clinical trials     

Idiopathic pulmonary fibrosis: Current and future treatment

ObjectivesIdiopathic pulmonary fibrosis (IPF) is a chronic fibrotic lung disease characterized by dry cough, fatigue, and progressive exertional dyspnea. Lung parenchyma and architecture is destroyed, compliance is lost, and gas exchange is compromised in this debilitating condition that leads inexorably to respiratory failure and death within 3–5 years of diagnosis. This review discusses treatment approaches to IPF in current use and those that appear promising for future development.Data SourceThe data were obtained from the Randomized Controlled Trials and scientific studies published in English literature. We used search terms related to IPF, antifibrotic treatment, lung transplant, and management.ResultsEtiopathogenesis of IPF is not fully understood, and treatment options are limited. Pathological features of IPF include extracellular matrix remodeling, fibroblast activation and proliferation, immune dysregulation, cell senescence, and presence of aberrant basaloid cells. The mainstay therapies are the oral antifibrotic drugs pirfenidone and nintedanib, which can improve quality of life, attenuate symptoms, and slow disease progression. Unilateral or bilateral lung transplantation is the only treatment for IPF shown to increase life expectancy.ConclusionClearly, there is an unmet need for accelerated research into IPF mechanisms so that progress can be made in therapeutics toward the goals of increasing life expectancy, alleviating symptoms, and improving well‐being.     

Mechanistic links between aging and lung fibrosis

Our understanding of the biology of aging has advanced significantly in recent years. This has resulted in the recent formulation of the “hallmarks of aging” that include genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, deregulated nutrient sensing, mitochondrial dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication. Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease that results from the accumulation of scar tissue in the lungs of affected individuals. IPF is a disease of aging that most commonly affects human subjects older than 60 years of age. While progress has been made in elucidating key pathological processes in IPF, the relationship of these processes to those that occur during aging are not well defined. In this review, we explore existing and emerging paradigms in the pathogenesis of IPF in light of the recently defined hallmarks of aging.     

Lower occurrence of idiopathic pulmonary fibrosis in Maori and Pacific Islanders

OBJECTIVE: Idiopathic pulmonary fibrosis (IPF), a chronic fibro-proliferative interstitial pneumonia, has not been reported to occur more frequently in any particular race. We have observed that our patients with IPF comprise a proportionately lower number of Maori and Pacific Islanders and set out to evaluate this further. METHODS: Retrospective analysis of an IPF database from a single tertiary respiratory institution was undertaken. Demographic and survival data were collected. Ethnicity was compared with 2001 New Zealand census data from the same catchment area. RESULTS: Eighty-seven cases of IPF were identified. Overall median survival was 46 months. Ethnicity data were available for 84 of the 87 cases. 76/84 (90%) were European, 6/84 (7%) were Asian or Indian, 2/84 (2%) were Maori, and 0/84 (0%) were Pacific Islanders. For Maori and Pacific Islanders, this represented a significant trend in difference when compared with ethnicity data from the hospital catchment population (P < 0.001). CONCLUSIONS: Our department is the tertiary referral centre for pulmonary disease in the upper North Island of New Zealand, and therefore referral centre bias is likely to be low. The preliminary observation that the occurrence of IPF is lower in those of Maori or Polynesian ethnicity warrants further study. This may, in part, help in our understanding of the pathogenic mechanisms in IPF.     

Review series: Aspects of interstitial lung disease: connective tissue disease-associated interstitial lung disease: how does it differ from IPF? How should the clinical approach differ?

The lung is frequently involved in connective tissue diseases (CTDs), although the frequency of lung manifestations varies according to the type of CTD. Interstitial lung diseases (ILD) are frequently seen in CTDs, particularly systemic sclerosis (SSc), polymyositis/dermatomyositis (PM/DM) and rheumatoid arthritis (RA), accounting for a significant proportion of deaths. A large percentage of patients with CTD-associated ILD has limited and stable disease, not requiring treatment. However, a significant minority has severe and/or progressive disease, necessitating prompt initiation of treatment. CTD-ILD histological patterns include non-specific interstitial pneumonia (NSIP), usual interstitial pneumonia (UIP), organizing pneumonia (OP), diffuse alveolar damage (DAD) and lymphocytic interstitial pneumonia (LIP). NSIP is the most common pattern in all CTDs, except for RA, characterized by a higher frequency of UIP. ILD can present acutely or chronically, with acute presentations being more common in systemic lupus erythematosus and PM/DM. Idiopathic pulmonary fibrosis (IPF) is a progressively worsening ILD characterized by inflammation and fibrosis. The characteristic histological pattern of IPF is UIP. Interestingly, a UIP pattern is associated with a significantly better survival in CTD-related disease compared to the idiopathic variety. Prognosis in IPF is dismal, with a median survival since diagnosis of 2-3 years. No treatment regimen has been shown to improve survival in IPF. By contrast, although there have been only two randomized placebo-controlled trials investigating the effect of immunosuppressive treatment in SSc-associated ILD, clinical experience suggests that immunosuppressive drugs in CTD-related ILDs are capable of benefiting a significant proportion of patients, particularly those with certain histological patterns of disease. This review will essentially focus on CTD-associated ILD and will compare aspects of clinical presentation and management to those of IPF.     

Clinical review: idiopathic pulmonary fibrosis--past, present and future

Idiopathic pulmonary fibrosis (IPF) is an important, and devastating, interstitial lung disease. It has a median mortality of only 3 years, worse than many cancers, and its incidence continues to rise. In this article, an overview of key developments in our understanding and clinical management of IPF will be provided.     

Determinants of initiation and progression of idiopathic pulmonary fibrosis

IPF is a devastating disease with few therapeutic options. The precise aetiology of IPF remains elusive. However, our understanding of the pathologic processes involved in the initiation and progression of this disease is improving. Data on the mechanisms underlying IPF have been generated from epidemiologic investigations as well as cellular and molecular studies of human tissues. Although no perfect animal model of human IPF exists, pre-clinical animal studies have helped define pathways which are likely important in human disease. Epithelial injury, fibroblast activation and repetitive cycles of injury and abnormal repair are almost certainly key events. Factors which have been associated with initiation and/or progression of IPF include viral infections, abnormal cytokine, chemokine and growth factor production, oxidant stress, autoimmunity, inhalational of toxicants and gastro-oesophageal reflux disease. Furthermore, recent evidence identifies a role for a variety of genetic and epigenetic abnormalities ranging from mutations in surfactant protein C to abnormalities in telomere length and telomerase activity. The challenge remains to identify additional inciting agents and key dysregulated pathways that lead to disease progression so that we can develop targeted therapies to treat or prevent this serious disease.     

Guidelines on the management of common bile duct stones (CBDS)

The last 30 years have seen major developments in the management of gallstone-related disease, which in the United States alone costs over 6 billion dollars per annum to treat. Endoscopic retrograde cholangiopancreatography (ERCP) has become a widely available and routine procedure, whilst open cholecystectomy has largely been replaced by a laparoscopic approach, which may or may not include laparoscopic exploration of the common bile duct (LCBDE). In addition, new imaging techniques such as magnetic resonance cholangiography (MR) and endoscopic ultrasound (EUS) offer the opportunity to accurately visualise the biliary system without instrumentation of the ducts. As a consequence clinicians are now faced with a number of potentially valid options for managing patients with suspected CBDS. It is with this in mind that the following guidelines have been written.     

Current clinical trials for the treatment of idiopathic pulmonary fibrosis

Most pulmonary consultants are called upon to discuss IPF management with their patients. The gravity of IPF treatment discussion is immense in view of the data that 3‐ and 5‐year mortality rates are approximately 50% and 80%, respectively. Although IPF occurs in older patients with comorbid diseases, most patients with IPF die as a direct consequence of their lung fibrosis. Here, the results of recently completed IPF trials and the rationale for ongoing studies are succinctly reviewed. There are a number of novel agents in clinical trials that are in the earlier stages of development, and there is new evidence supporting palliative therapies, which may help in managing symptoms of IPF, such as cough, without necessarily altering the course of the disease. The information provided herein should facilitate informed physician–patient dialogue.     

Lupus: novel therapies in clinical development

There have been significant advancements in understanding the immunopathogenesis of systemic lupus erythematosus. However, the developments in therapeutics have been rather slow. Belimumab, a B lymphocyte stimulator (BLyS) inhibitor has been approved for the treatment of this disease after more than 50 years. Numerous biological agents are being developed which target the B cells, T cells, and various cytokines. Among anti-B cell therapy, drugs target CD20+ cells (ocrelizumab, SBI-087), CD22+ cells (epratuzumab) \or the receptors of tumor necrosis factor (TNF) superfamily (atacicept, LY2127399, A-623). Monoclonal antibodies targeting interferon alpha (IFN-α) and gamma (IFN-γ) and interleukins (IL-6, 10) are being investigated for SLE. Novel targets include toll like receptors, phosphodiesterases, CD40 ligand and retinoid receptors. This review discusses various drugs which are in different phases of clinical trials and hold promise for patients suffering from this chronic debilitating disease.     

Pulmonary hypertension in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an untreatable diffuse parenchymal lung disease with a median survival of < 3 years. Pulmonary hypertension (PH) is frequently seen in patients with IPF and is commonly attributed to hypoxic vasoconstriction and capillary destruction. Pathology findings include endothelial proliferation and medial hypertrophy that exceed those expected in the setting of hypoxia. Noninvasive evaluation has limited sensitivity and specificity for the diagnosis of PH in IPF; therefore, right-heart catheterization remains the "gold standard" diagnostic test. PH in patients with IPF is associated with decreased exercise capacity and worse survival. Given the grave consequences of this condition, treatment of PH could improve functional outcomes and survival. However, possible treatments such as long-term supplemental oxygen and targeted vascular therapy are either unstudied or remain unproven.     

What parameters can be used to identify early idiopathic pulmonary fibrosis?

Elucidating the disease process of early idiopathic pulmonary fibrosis (IPF) will help clinicians in addressing the contentious issues of when and in which patients, therapeutic intervention should be initiated. Here, we discuss several possible parameters for diagnosing early IPF and their clinical impacts. Physiologically, early IPF can be considered as IPF with normal or mild impairment in pulmonary function. Radiologically, early IPF can be considered as IPF with a small extent and/or early features of fibrosis. Symptomatically, early IPF can be considered as asymptomatic or less symptomatic IPF. IPF at Gender-Age-Physiology index stage I can be considered early IPF. Interstitial lung abnormalities are defined as parenchymal abnormalities in more than 5% of the lung in patients with no prior history of interstitial lung disease, and in some cases, this seems to be equivalent to early IPF. Previous clinical trials showed the effect of antifibrotic therapies in early IPF, but the effects of therapy are uncertain in early IPF outside of clinical trials, such as in cases of IPF with normal pulmonary function, IPF without honeycombing or traction bronchiectasis, and asymptomatic IPF. Moreover, little has been reported on disease progression in such conditions. Because the conceptual framework of early IPF may vary depending on its definition, not only is a diagnosis of early IPF important but prediction of disease progression is also crucial. Further investigations are needed to identify biomarkers that can detect patients who may experience greater degrees of disease progression and require treatment even with those forms of early IPF.     

Progress toward improving animal models for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) remains a disease with an unknown cause and a poor prognosis. Among attempts to define disease pathogenesis, animal models of experimental lung fibrosis have a prominent role. Commonly used models include exposure to bleomycin, silica, fluorescein isothiocyanate; irradiation; or expression of specific genes through a viral vector or transgenic system. These all have been instrumental in the study of lung fibrosis, but all have limitations and fall short of recapitulating a pattern of usual interstitial pneumonia, the pathologic correlate to IPF. A model of repetitive bleomycin lung injury has recently been reported that results in marked lung fibrosis, prominent alveolar epithelial cell hyperplasia, a pattern of temporal heterogeneity and persistence of aberrant remodeling well after stimulus removal, representing a significant addition to the collection of animal lung fibrosis models. Taken together, animal models remain a key component in research strategies to better define IPF pathogenesis.     

Idiopathic pulmonary fibrosis: an altered fibroblast proliferation linked to cancer biology

The fibrotic process that characterizes idiopathic pulmonary fibrosis (IPF) is commonly considered the result of a recurrent injury to the alveolar epithelium followed by an uncontrolled proliferation of fibroblasts. However, based on considerable scientific evidence, it has been recently hypothesized that IPF might be considered a neoproliferative disorder of the lung because this disease exhibits several pathogenic features similar to cancer. Indeed, epigenetic and genetic abnormalities, altered cell-to-cell communications, uncontrolled proliferation, and abnormal activation of specific signal transduction pathways are biological hallmarks that characterize the pathogenesis of IPF and cancer. IPF remains a disease marked by a survival of 3 years, and little therapeutic progress has been made in the last few years, underlining the urgent need to improve research and to change our approach to the comprehension of this disease. The concept of IPF as a cancer-like disease may be helpful in identifying new pathogenic mechanisms that can be borrowed from cancer biology, potentially leading to different and more effective therapeutic approaches. Such vision will hopefully increase the awareness of this disease among the public and the scientific community.     

特发性肺纤维化急性加重

特发性肺纤维化(idiopathic pulmonary fibrosis,IPF)是最常见的一种特发性间质性肺炎,目前病因不明,组织病理表现为普通型问质性肺炎.既往认为IPF是一个逐渐进展的疾病,后来认识到部分IPF患者在病程中可以无明显原因出现症状的急剧恶化,这种现象被称为 IPF急性加重(acute exacerbations of IPF,AE-IPF).最近,AE-IPF得到了广泛的重视和研究.本文将对AE-IPF的发病率和病死率、病因、临床特点、病理改变、诊断和治疗进展等方面作一综述.     

Acute exacerbations of idiopathic pulmonary fibrosis

The natural history of idiopathic pulmonary fibrosis (IPF) has been characterized as a steady, predictable decline in lung function over time. Recent evidence suggests that some patients may experience a more precipitous course, with periods of relative stability followed by acute deteriorations in respiratory status. Many of these acute deteriorations are of unknown etiology and have been termed acute exacerbations of IPF. This perspective is the result of an international effort to summarize the current state of knowledge regarding acute exacerbations of IPF. Acute exacerbations of IPF are defined as acute, clinically significant deteriorations of unidentifiable cause in patients with underlying IPF. Proposed diagnostic criteria include subjective worsening over 30 days or less, new bilateral radiographic opacities, and the absence of infection or another identifiable etiology. The potential pathobiological roles of infection, disordered cell biology, coagulation, and genetics are discussed, and future research directions are proposed.     

Idiopathic pulmonary fibrosis. Abnormalities in the bronchoalveolar lavage content of surfactant protein A

Idiopathic pulmonary fibrosis (IPF) is a progressive disease of the lung characterized by an inflammatory infiltrate, alveolar type II cell hypertrophy and hyperplasia, and ultimate parenchymal scarring. The phospholipid composition of the surface-active material recovered by bronchoalveolar lavage (BAL) is abnormal in this disease. In the present study we have extended the analysis of surfactant components in IPF to include the major surfactant-associated protein, surfactant protein A (SP-A). SP-A has been reported to be essential for the formation of tubular myelin, to facilitate the adsorption of phospholipid to the air/liquid interface, and to stimulate uptake and inhibit secretion of surfactant in vitro. The BAL of 25 normal volunteers and 42 patients with interstitial lung disease (ILD) was analyzed for surfactant protein A content by ELISA and for phospholipids. The changes in BAL components were correlated to histopathologic markers at open-lung biopsy, clinical status, and survival. The total phospholipid (PL) recovered at lavage was reduced in patients with IPF relative to normal volunteers (p less than 0.0005). In addition, the percentage of phosphatidyl-glycerol (% PG) was decreased in patients with IPF (p less than 0.0001), whereas the percentage of phosphatidylcholine that was saturated was not altered. The content of surfactant protein A in lavage was reduced, even when normalized for the total amount of surface-active material recovered (SP-A/PL) (p less than 0.007). The reduction in SP-A was not specific to IPF but also occurred in other interstitial lung diseases.(ABSTRACT TRUNCATED AT 250 WORDS)     

Epigenetic mechanisms through which Toll-like receptor-9 drives idiopathic pulmonary fibrosis progression

Patients with idiopathic pulmonary fibrosis (IPF) survive a median of 3 years after diagnosis, but a high degree of variability in longitudinal disease progression has been observed. Unfortunately, physiology and clinical parameters determined at the time of diagnosis have proven inaccurate in predicting the rate at which IPF ultimately progresses. A mechanistic explanation for disease progression in patients with IPF is presently unclear, but we have recently shown that hypomethylated CpG DNA drives the rapid progression of fibrotic lung disease through the differentiation of pulmonary fibroblasts into myofibroblasts through a TLR9-dependent mechanism. Furthermore, we recently reported that the clinical progression of IPF might be a consequence of aberrant microRNA processing. Using this framework of data, we are presently addressing the following specific hypothesis: hypomethylated CpG DNA activation in pulmonary fibroblasts leads to aberrant micro RNA processing, thereby promoting the rapid progression of IPF.     

Recent advances in idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) remains the most common of the idiopathic interstitial pneumonias and portends a poor prognosis. Significant strides have been made in the approach to diagnosis and in the ability to predict outcome in the last few years. Advances in high-resolution CT (HRCT) scanning have allowed an accurate diagnosis obviating the need for surgical biopsy in many patients. Furthermore, HRCT scanning may aid in determining prognosis and identifying disease progression. The appropriate use of the HRCT scan requires a multidisciplinary iterative approach incorporating all available data to reach a final diagnosis. However, there remains great heterogeneity in disease progression. Pulmonary hypertension and acute exacerbations of IPF negatively influence prognosis and are increasingly a target of therapy. There has been an increase in the number of well-designed clinical trials of IPF that have focused on more specific targets. While no cure has yet been found, each trial expands our understanding regarding the natural course of the disease and the impact of targeted therapy. In the interim, lung transplantation, which appears to improve survival in a subset of IPF patients, remains the only intervention. The objective of this article is to review advances in the understanding of IPF and the evidence for the findings outlined above.