Interferon-γ 1b: impact of new indications (idiopathic pulmonary fibrosis)

Idiopathic pulmonary fibrosis (IPF) is a relentlessly progressive disease with inadequate response to conventional treatment with corticosteroids and/or immunosuppressive agents in most patients. Interferon-γ (IFN-γ), an antifibrotic agent, has been proposed as a novel therapeutic approach. Several investigators have shown a relative decrease in systemic and pulmonary IFN-γ activity in patients with IPF. Experimental evidence from animal and human studies also suggests that IFN-γ administration may ameliorate lung fibrosis. Clinical experience is, however, limited to a single clinical trial that showed objective functional improvement in a small number of patients treated with IFN-γ and low-dose corticosteroids. Further research is needed to characterise the efficacy, safety and optimum route of administration of this agent before it can be recommended for use in routine clinical practice.     

Pirfenidone for the treatment of idiopathic pulmonary fibrosis: therapeutic potential prompts further investigation

Idiopathic pulmonary fibrosis (IPF) is a rare, progressive disease of the lungs with unknown aetiology. Currently, there is no therapy that is specifically approved to be used for IPF treatment and the efficacy of ‘conventional therapy’, recommended by the existing therapeutic guidelines and consisting of a combination of corticosteroids with immunosuppressives, is not sufficiently substantiated. Based on the current pathogenetic hypothesis advocating the major role of fibrosis in IPF, novel antifibrotic agents are being developed for the treatment of this disease. Among them, IFN-γ and N-acetylcysteine are at later stages of clinical development. Pirfenidone is another antifibrotic agent that has also demonstrated preclinical anti-inflammatory and antioxidant effects. Earlier clinical studies showed that prifenidone could be efficacious for IPF treatment. Pirfenidone acquired orphan drug status in both Europe and the US for the treatment of IPF. The current randomised, placebo-controlled study authored by Azuma et al. further assesses its efficacy in IPF patients and searches for new potential efficacy end points in this setting.     

Pirfenidone for the treatment of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is an under-recognised, rare, progressive disease of the lungs with unknown aetiology and high mortality. The currently advocated pathogenic mechanism is represented by progressive multifocal fibrosis. It is diagnosed based on clinical, radiographic, physiological and histopathological criteria. Existing therapeutic guidelines recommend anti-inflammatory and immunosuppressive combinations, despite proven limited efficacy. There is no therapy approved specifically for IPF, but several antifibrotic agents are currently under development for this indication. Pirfenidone is an antifibrotic agent potentially effective for IPF therapy, and preclinical and available clinical data support its use in IPF. Future clinical studies are expected to provide more consistent information on survival benefit, lung function and health-related quality of life.     

Precision medicine in idiopathic pulmonary fibrosis therapy: From translational research to patient-centered care

Idiopathic pulmonary fibrosis (IPF) is a progressive, irreversible fibrotic chronic lung disease affecting predominantly older adults, with a history of smoking. The current model of disease natural course is that recurrent injury of the alveolar epithelium in the context of advanced aging/cellular senescence is followed by defective re-epithelialization and scar tissue formation. Currently, two drugs, nintedanib and pirfenidone, that modify disease progression have been approved worldwide for the treatment of IPF. However, despite treatment, patients with IPF are not cured, and eventually, disease advances in most treated patients. Enhancing biogenomic and metabolic research output, its translation into clinical precision and optimal service delivery through patient-centeredness are key elements to support effective IPF care. In this review, we summarize therapeutic options currently investigated for IPF based on the major pathogenetic pathways and molecular targets that drive pulmonary fibrosis.     

间充质干细胞治疗特发性肺纤维化药理机制研究进展

间充质干细胞（MSCs）具有多种分化能力,可以直接迁移到损伤组织中并分化为肺泡上皮细胞,还可以分泌并释放多种细胞因子和外泌体,调节炎症和免疫反应。特发性肺纤维化（IPF）是与年龄相关、发病机制尚不明确的慢性进行性肺部疾病,临床上使用的吡非尼酮和尼达尼布仅能缓解症状。MSCs在治疗IPF方面具有广阔的应用前景,就目前关于MSCs治疗特发性肺纤维化的药理机制以及该疗法所存在的局限性进行综述和探讨。     

自噬调节与特发性肺纤维化药物治疗研究进展

特发性肺纤维化（idiopathic pulmonary fibrosis，IPF）是一种病因复杂、与年龄相关的肺纤维化疾病，其发病过程表现出进行性与不可逆性，最终导致患者呼吸系统衰竭而死亡。近些年的研究证实自噬参与了IPF的发生发展。本文回顾总结了自噬和IPF相关的临床研究、动物和细胞模型研究以及基于自噬的药物治疗研究，希望对阐明IPF的病理机制和药物研发有所帮助。     

Idiopathic pulmonary fibrosis: pathogenesis and therapeutic approaches

Idiopathic pulmonary fibrosis (IPF), also termed cryptogenic fibrosing alveolitis, is a clinicopathological syndrome characterised by cough, exertional dyspneoa, basilar crackles, a restrictive defect on pulmonary function tests, honeycombing on high-resolution, thin-section computed tomographic scans and the histological diagnosis of usual interstitial pneumonia on lung biopsy. The course is usually indolent but inexorable. Most patients die of progressive respiratory failure within 3-8 years of the onset of symptoms. Current therapies are of unproven benefit. Although the pathogenesis of IPF has not been elucidated, early concepts focused on lung injury leading to a cycle of chronic alveolar inflammation eventuating in fibrosis and destruction of the lung architecture. Anti-inflammatory therapies employing corticosteroids or immunosuppressive or cytotoxic agents have been disappointing. More recent hypotheses acknowledge that sequential alveolar epithelial cell injury is likely to be a key event in the pathogenesis of IPF, but the cardinal event is an aberrant host response to wound healing. In this context, abnormal epithelial-mesenchymal interactions, altered fibroblast phenotypes, exaggerated fibroblast proliferation, and excessive deposition of collagen and extracellular matrix are pivotal to the fibrotic process. Several clinical trials are currently underway or in the planning stages, and include drugs such as interferon-gamma 1b, pirfenidone, acetylcysteine, etanercept (a tumor necrosis factor-alpha antagonist), bosentan (an endothelin-1 receptor antagonist) and zileuton (a 5-lypoxygenase inhibitor). Future therapeutic strategies should be focused on alveolar epithelial cells aimed at enhancing re-epithelialisation and on fibroblastic/myofibroblastic foci, which play an essential role in the development of IPF. Stem cell progenitors of the alveolar epithelial cells and genetic and epigenetic therapies are attractive future approaches for this and other fibrotic lung disorders.     

S1PR1 serves as a viable drug target against pulmonary fibrosis by increasing the integrity of the endothelial barrier of the lung

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with unclear etiology and limited treatment options. The median survival time for IPF patients is approximately 2–3 years and there is no effective intervention to treat IPF other than lung transplantation. As important components of lung tissue, endothelial cells (ECs) are associated with pulmonary diseases. However, the role of endothelial dysfunction in pulmonary fibrosis (PF) is incompletely understood. Sphingosine-1-phosphate receptor 1 (S1PR1) is a G protein-coupled receptor highly expressed in lung ECs. Its expression is markedly reduced in patients with IPF. Herein, we generated an endothelial-conditional S1pr1 knockout mouse model which exhibited inflammation and fibrosis with or without bleomycin (BLM) challenge. Selective activation of S1PR1 with an S1PR1 agonist, IMMH002, exerted a potent therapeutic effect in mice with bleomycin-induced fibrosis by protecting the integrity of the endothelial barrier. These results suggest that S1PR1 might be a promising drug target for IPF therapy.     

Interstitial pulmonary fibrosis in an automobile body shop worker

Interstitial pulmonary fibrosis (IPF) is often of uncertain etiology and is therefore named 'idiopathic' pulmonary fibrosis. Some occupational exposures, however, are known to cause interstitial fibrosis, asbestos and silica being well-known examples. We present clinical and pathological findings of a case with IPF and the results of microchemical analysis of inorganic particulate matter in the lung tissue. A very high lung burden of inorganic contaminants was found, including silica and metallic compounds. Emphasis is given to the importance of obtaining detailed occupational histories and conducting microchemical analysis of lung tissue in order to clarify etiological factors in cases with 'idiopathic' pulmonary fibrosis.     

干扰素γ治疗肝和肺纤维化

实验室、动物试验和临床研究表明,干扰素γ(Interferon gamma,IFN-γ)对肝和肺纤维化有抑制作用.国内外学者报告用IFN-γ治疗各种原因引起的肝纤维化有效,临床症状明显改善,肝纤维化程度明显减轻.IFN-γ治疗特发性肺纤维化的初步结果显示,治疗后各种生物学指标有所改善,临床效果各家报道不一,多数学者认为IFN-γ治疗能降低病死率,对病情轻到中度的患者效果较好,用药时间应在1年以上.     

Update on models of pulmonary fibrosis therapy for preclinical drug research

Background: Idiopathic pulmonary fibrosis (IPF) is a disease with high morbidity and mortality for which current medications are not effective. Therefore, identification of potential therapies is of paramount importance. The preclinical evaluation of novel compounds in animal models represents a critical step in drug development. Objective: To describe features and limitations of common animal models of pulmonary fibrosis and discuss relevant preclinical and clinical data on novel potential IPF therapies. Methods: Review of the existing literature on such models with a special focus on the bleomycin model and its usefulness for the IPF preclinical drug testing. Conclusions: The model of bleomycin-induced pulmonary fibrosis has the advantages of being well established, reproducible and both time- and cost-efficient. However, it has major limitations as it only mimics some features of human IPF. Most importantly, it is initiated by acute lung injury and is at least partially reversible, which is strikingly different from IPF. The failure in establishing effective IPF therapies despite strong efforts in the last decade is partly attributable to our uncritical trust in the models of lung fibrosis and the false belief that they truly reflect what is going on in human disease.     

特发性肺间质纤维化的CT临床诊断回顾性队列追踪研究

目的探讨特发性肺间质纤维化CT临床诊断。方法采用流行病学回顾性队列追踪研究方法,进行个体化问卷调查表。结果 CT可见病变累及上叶和下叶,中下野明显较多,背侧更为明显,呈清晰的外周分布,重者或涉及肺中带。101例均出现清晰可见网状结节影,结节直径2～3mm,边缘模糊,网络相连。28例有明显蜂窝改变占27.72%,11例有磨玻璃改变占10.89%,13例有局限性胸膜增厚占12.87%。结论特发性肺间质纤维化（IPF）临床CT临床诊断非常重要,其肺部CT表现及病理改变为为深入和全面了解患者的治疗与转归工作提供一线临床基础资料。     

Recent advances in particulate-induced pulmonary fibrosis; for the application of possible strategy experimentally and clinically

Chronic interstitial lung diseases including pneumoconiosis have pathological characteristics which alter the lung structure and function consequent to the accumulation and activation of inflammatory cells in the lower respiratory tract. These activated cells usually secrete the inflammatory and fibrogenic mediators. Of the diffuse parenchymal lung diseases, the majority have no known etiology and idiopathic pulmonary fibrosis (IPF) is the diagnosis most frequently encountered by clinicians. Pathogenic similarities between pneumoconiosis and IPF provide a strong basis for hypothesizing that environmental agents may cause IPF. Many case-control studies have been published that provide further evidence for a number of associations between occupational and environmental exposures and IPF. Such reports support a strong evidence that IPF may be a heterogenous disorder associated with a number of environmental exposures. As a model of lung fibrosis, experimental pneumoconiosis is giving us a great information because crystalline silica is probably one of the most typical agent producing pulmonary fibrosis and the severity of its health effects and the widespread nature of exposure have been long recognized. Many papers provide evidence that particles have the potential to cause stimulation of phagocytes to release oxidants and such oxidative stress is believed to be a major factor in pulmonary inflammation followed by fibrotic change. Many kinds of cellular mediators are recognized as a implicating factor in this process including cell-to-cell interaction, enzymes, cytokines, arachidonic acid derivatives et al. Treatment of pneumoconiosis is an attractive and interesting topic. But, the mechanism of pathogenesis of pneumoconiosis is not thoroughly understood yet. Also, whether the process of fibrosis formation be retarded or not is questionable with some therapeutic trial. Therefore, a sensitive biomarker which is possible to estimate the pathological pathway in pneumoconiosis is needed. Our laboratory has studied particulate-induced pulmonary reaction for two decades consistently. This review will focus on signal transduction pathway involved in oxidative stress and some inhibitory agents with pleiotropic mechanism in pulmonary fibrosis. I will also introduce some data of animal studies with multidrug regimen as well.     

Bosentan for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF) is a debilitating, fatal, chronic fibrosing lung disease with no known effective therapy. Endothelin-1 may underlie the pathogenesis of lung fibrosis, therefore it was hypothesized that the oral dual endothelin receptor antagonist bosentan may have efficacy for the treatment of IPF. The BUILD-1 study evaluated the efficacy, safety and tolerability of bosentan in patients with IPF. Bosentan was associated with a trend toward delayed time to disease progression or death and improvement in quality-of-life, both of which were more pronounced in patients with a biopsy-confirmed IPF diagnosis. These observations are being investigated in the ongoing BUILD-3 trial.     

Association of serum macrophage-mannose receptor CD206 with mortality in idiopathic pulmonary fibrosis

BackgroundAcute exacerbation of idiopathic pulmonary fibrosis (AE-IPF) is attracting considerable attention due to disease acceleration and substantial mortality. Macrophages are known to regulate the fibrotic process in idiopathic pulmonary fibrosis.ObjectiveWe investigated if two new macrophage-specific serum biomarkers, soluble mannose receptor (MR, sCD206) and soluble CD163 (sCD163), increased in serum obtained from patients with AE-IPF compared to stable IPF (S-IPF).MethodsA total of 36 IPF patients with AE status, 54 IPF patients with stable status, and 27 normal controls were enrolled in this study. The levels of serum sCD206 and sCD163 were compared among the three groups and analysed with the clinical features and mortality of IPF.ResultsThe serum concentrations of both markers were higher in patients with AE-IPF than in those with S-IPF (580.0 ng/ml vs 335 ng/ml for sCD206 and 69.2 ng/ml vs 37.9 ng/ml for sCD163). The level of sCD206 was related to an increased risk of mortality (HR = 1.002, p < 0.001). The best separation between decedents and survivors was obtained by sCD206 (area under the receiver operating characteristic curve [AUC] 0.712 and 95% confidence interval 0.595–0.830).ConclusionOur data demonstrated that the macrophage-related markers sCD206 and sCD163 were significantly higher in patients with IPF, especially sCD206 in AE-IPF patients. The high level of serum sCD206 was associated with mortality in idiopathic pulmonary fibrosis.     

特发性肺间质纤维化合并社区获得性肺炎患者的药学监护实践

目的探讨特发性肺间质纤维化并社区获得性肺炎患者的药学监护模式。方法结合特发性肺间质纤维化治疗研究进展,介绍参与1例特发性肺间质纤维化并社区获得性肺炎患者药学监护的经验。结果临床药师与医师一同制定药物治疗方案,对患者进行药学监护,提供药学服务,提高了患者的治疗效果,减少了药物不良反应的发生。结论通过临床药师实施药学监护,可及时发现患者的药物治疗问题,促进临床合理用药,对延缓病程发展,提高患者生活质量有重要意义。     

Systematic review: the relationship between interstitial lung diseases and gastro-oesophageal reflux disease

BACKGROUND A potential relationship has been suggested between gastro-oesophageal reflux disease (GERD) and interstitial lung diseases (ILDs). AIM To evaluate whether there is a causal relationship between GERD and different ILDs. METHODS We conducted a systematic search of literature published between 1980 and 2010. After a review by two independent authors, each study was assigned an evidence-based rating according to a standard scoring system. RESULTS We identified 319 publications and 22 of them met the entry criteria. Of those, the relationship between GERD and idiopathic pulmonary fibrosis (IPF) was investigated in 14 articles, pulmonary involvement in systemic sclerosis (SSc) in six articles and pulmonary involvement in mixed connective tissue disease (MCTD) in two articles. We found the prevalence of GERD and/or oesophageal dysmotility to be higher in patients with different types of ILD as compared with those without ILD [Evidence B]. Among patients with IPF, 67-76% demonstrated abnormal oesophageal acid exposure off PPI treatment. No relationship was demonstrated between severity of GERD and severity of IPF [Evidence B]. Data are scant on outcomes of antireflux treatment in patients with IPF. There is a correlation between the severity of ILD and the degree of oesophageal motor impairment in patients with SSc and MCTD [Evidence B]. CONCLUSIONS Based on the currently available data, a causal relationship between GERD and idiopathic pulmonary fibrosis cannot be established. There is scant evidence about antireflux therapy in idiopathic pulmonary fibrosis patients. There may be an association between lung and oesophageal involvement in systemic sclerosis and mixed connective tissue disease, but a causal relationship cannot be established.     

Targeting the endothelin pathway in the idiopathic pulmonary fibrosis: the role of bosentan

Background: Idiopathic pulmonary fibrosis (IPF) is a rapidly lethal disease characterized by anarchic, progressive fibrosis. Pulmonary fibrosis is the result of interactions between many effector cells and cytokines and better understanding of this can help with identification of novel therapeutic targets. Objective: To evaluate the role of the endothelin-1 (ET-1) pathway in IPF pathogenesis and the effects of therapeutic targeting with bosentan, an ET-1 antagonist. Methods: Data on ET-1's pathogenic involvement in IPF and the preclinical and clinical data on bosentan in this context are discussed and analyzed. A parallel overview of existing and upcoming therapies for IPF is presented. Conclusions: Bosentan is a promising antifibrotic therapy for IPF and clinical data on its long-term efficacy support its use.     

重组人干扰素-γ联合激素治疗特发性肺间质纤维化临床观察

目的观察重组人干扰素-γ(IFN-γ)联合激素治疗特发性肺间质纤维化(IPF)患者的疗效。方法选择IPF患者56例及健康对照人群15例,将56例IPF患者随机分为激素治疗组和IFN-γ联合治疗组,测定IPF患者及健康对照人群的Ⅲ型胶原(Ⅲ-C)、Ⅳ型胶原(Ⅳ-C)、透明质酸(HA)的含量;比较激素治疗组和IFN-γ联合治疗组患者治疗前后临床症状、肺CT、肺弥散功能、血清纤维化指标的变化。结果 IPF患者治疗前血清Ⅲ-C、Ⅳ-C、HA的水平明显高于健康对照组(P<0.01);联合治疗组及激素治疗组治疗后患者呼吸困难好转,活动能力提高,肺弥散功能改善,血清Ⅲ-C、Ⅳ-C、HA水平较治疗前降低(P<0.05或<0.01),联合治疗组改善程度及血纤维化指标降低程度与激素治疗组比较差异有统计学意义(P<0.05),2组胸部CT有不同程度的病变吸收,差异无统计学意义(P>0.05)。结论 IFN-γ联合激素治疗可改善IPF患者临床症状及肺纤维化程度,其疗效优于单纯激素治疗组。     

Predictors of mortality of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis (IPF), a disease with histological features corresponding to usual interstitial pneumonia (UIP), is a disorder of unknown cause. Not only it is the most common subtype of idiopathic interstitial pneumonias but it is also associated with the highest mortality rate. Despite a good number of studies investigating the mortality of patients with UIP the prognostic factors that have been studied have several limitations. To date it is unclear when in the course of the disease and with what modality these patients should be treated. According to the literature we subcategorized predictors of mortality into (a) baseline predictors; (b) dynamic predictors. IPF perspectives in therapy have been also analyzed. Moreover, the principal aims of this review were: (1) to analyze and to clarify the clinical utility of different prognostic factors for IPF; (2) to enable clinicians to better evaluate the eligibility criteria for lung transplantation in the clinical practice.