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.     

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.     

Interferon-gamma 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-gamma (IFN-gamma), an antifibrotic agent, has been proposed as a novel therapeutic approach. Several investigators have shown a relative decrease in systemic and pulmonary IFN-gamma activity in patients with IPF. Experimental evidence from animal and human studies also suggests that IFN-gamma 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-gamma 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.     

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.     

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.     

N-乙酰半胱氨酸治疗慢性阻塞性肺疾病合并肺间质纤维化疗效探讨

目的：探讨N-乙酰半胱氨酸治疗慢性阻塞性肺疾病（COPD）合并肺间质纤维化（IPF）的疗效。方法将142例COPD合并IPF患者随机均分为观察组和对照组,对照组给予氨茶碱片、盐酸氨溴索片等常规治疗,观察组加用N-乙酰半胱氨酸治疗,观察两组治疗效果。结果观察组治疗后CRP评分低于对照组（P＜0.05）;观察组患者治疗后FEV1、VC、DLCO、PaO2及TGF-β1优于对照组（P＜0.05）;观察组治疗总有效率为83.10%,明显高于对照组的59.15%（P＜0.05）。结论 N-乙酰半胱氨酸可抑制COPD合并IPF患者肺纤维化,改善肺功能及PaO2水平。     

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.     

Intrinsic defence capacity and therapeutic potential of natriuretic peptides in pulmonary hypertension associated with lung fibrosis

BACKGROUND AND PURPOSE

Idiopathic pulmonary fibrosis (IPF) is a progressive fibro-proliferative disorder refractory to current therapy commonly complicated by the development of pulmonary hypertension (PH); the associated morbidity and mortality are substantial. Natriuretic peptides possess vasodilator and anti-fibrotic actions, and pharmacological augmentation of their bioactivity ameliorates renal and myocardial fibrosis. Here, we investigated whether natriuretic peptides possess an intrinsic cytoprotective function preventing the development of pulmonary fibrosis and associated PH, and whether therapeutics targeting natriuretic peptide signalling demonstrate efficacy in this life-threatening disorder.

EXPERIMENTAL APPROACH

Pulmonary haemodynamics, right ventricular function and markers of lung fibrosis were determined in wild-type (WT) and natriuretic peptide receptor (NPR)-A knockout (KO) mice exposed to bleomycin (1 mg·kg⁻¹). Human myofibroblast differentiation was studied in vitro.

KEY RESULTS

Exacerbated cardiac, vascular and fibrotic pathology was observed in NPR-A KO animals, compared with WT mice, exposed to bleomycin. Treatment with a drug combination that raised circulating natriuretic peptide levels (ecadotril) and potentiated natriuretic peptide-dependent signalling (sildenafil) reduced indices of disease progression, whether administered prophylactically or to animals with established lung disease. This positive pharmacodynamic effect was diminished in NPR-A KO mice. Atrial natriuretic peptide and sildenafil synergistically reduced TGFβ-induced human myofibroblast differentiation, a key driver of remodelling in IPF patients.

CONCLUSIONS AND IMPLICATIONS

These data highlight an endogenous host-defence capacity of natriuretic peptides in lung fibrosis and PH. A combination of ecadotril and sildenafil reversed the pulmonary haemodynamic aberrations and remodelling that characterize the disease, advocating therapeutic manipulation of natriuretic peptide bioactivity in patients with IPF.     

Nintedanib for the treatment of idiopathic pulmonary fibrosis

Introduction: Idiopathic Pulmonary Fibrosis (IPF) is an interstitial lung disease characterized by the progressive loss of pulmonary function, ultimately leading to respiratory failure and death. Two novel compounds, nintedanib and pirfenidone, have shown efficacy in reducing the rate of decline of lung function in IPF patients. The multiple tyrosine kinase inhibitor nintedanib has extensively being studied as a potential angiogenesis inhibitor in clinical against various neoplastic disorders. Afterwards, this compound was successfully tested in IPF.

Areas covered: Herein, the authors review the working mechanisms of nintedanib, its pharmacological profile, and its efficacy and safety for patients with IPF.

Expert opinion: Nintedanib has shown to be safe and effective in patients with IPF, with a favorable long-term safety profile. There is a lack of comparative trials of pirfenidone and nintedanib, and the choice of treatment is left to the physicians’ judgement. Future directions of nintedanib use are represented by the treatment of progressive fibrosing interstitial lung disease other than IPF, IPF with advanced functional impairment, and lung fibrosis secondary to connective tissue diseases. A promising safety profile for the combinational use of nintedanib and pirfenidone in IPF has also recently emerged.     

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.     

The role of urokinase in idiopathic pulmonary fibrosis and implication for therapy

Background: Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive and frequently fatal form of interstitial lung disease for which there are no proven drug therapies. The pathogenesis of IPF is complex and the urokinase-type plasminogen activator (uPA)/plasminogen system participates in the repair process. The balance between the activating enzyme uPA, and its inhibitor PAI-1, is a critical determinant of the amount of scar development that follows. Objective: To address the role of urokinase in the pathogenesis of pulmonary fibrosis and its implications for therapy. Methods: We reviewed a spectrum of therapeutic strategies and focused on fibrinolytic and anticoagulant drugs for IPF patients. Results/conclusion: There is currently a search for new pharmacotherapeutic agents that may modulate the fibrogenic pathways in IPF. Either blocking PAI-1 or using uPA itself may be a promising new therapeutic strategy.     

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.     

Use of transgenic mouse models to understand the origins of familial pulmonary fibrosis

Pulmonary fibrosis is an unremitting degenerative lung disease that has an associated high mortality. The major pathological features include the growth of fibroblasts, emergence of myofibroblasts and their production of extracellular matrix that distorts the peripheral lung tissue and impairs respiratory function. Efforts to pharmacologically reduce inflammation, inhibit fibroblast growth, or matrix synthesis have not been successful in ameliorating disease. Genetic mutations associated with rare hereditary forms of interstitial lung disease (ILD) and idiopathic pulmonary fibrosis (IPF) link definitive causes to this enigmatic group of diseases. The generation of mouse models with similar genetic lesions or deficiencies is providing insight into the mechanisms that lead to fibrosis. Mutations that alter components of pulmonary surfactant or surfactant homeostasis have been associated with specific forms of ILD and/or IPF. This small but growing collection of IPF related surfactant dysfunction mutations implicate respiratory epithelial cell injury as an early event in the molecular pathogenesis and progression of fibrosis. Determining the mechanisms for genetically defined examples of IPF should be informative for investigating the larger segment of IPF where the underlying cause remains obscure.     

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.     

Bosentan

Bosentan (Tracleer), an orally administered dual endothelin (ET)(A) and ET(B) receptor antagonist, is indicated in the treatment of pulmonary arterial hypertension (PAH).The efficacy of oral bosentan 125 mg twice daily in improving exercise capacity has been demonstrated in well designed trials in adult patients with idiopathic PAH or PAH associated with connective tissue disease or congenital systemic-to-pulmonary shunts, and in other trials in patients with idiopathic PAH or PAH associated with congenital heart disease or HIV infection. The beneficial effects of first-line bosentan treatment may be maintained for up to 1 year in patients with idiopathic PAH or PAH associated with connective tissue disease. Despite the potential for treatment-related teratogenicity and hepatotoxicity, long-term data indicate that bosentan is generally well tolerated at the approved dosages. Although well designed trials are required to establish the efficacy of bosentan versus or in combination with other specific PAH therapies, especially sildenafil, the convenient oral administration and lack of serious injection-related adverse effects may render bosentan preferable to other PAH therapies. Preliminary data indicate that bosentan may be effective in pediatric PAH patients, although randomized trials are required. Furthermore, bosentan may be a useful option for the prevention of digital ulcer development in patients with systemic sclerosis. Thus, in accordance with current clinical guidelines, bosentan is a convenient, effective, and generally well tolerated agent for use in the first-line treatment of class III PAH or second-line treatment of class IV PAH.     

Emerging drugs for idiopathic pulmonary fibrosis

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.     

肺癌术后肺纤维化急性加重的诊疗进展

特发性肺纤维化（IPF）是一种特殊类型的间质性肺炎,以缓慢进展为特点,其病变局限在肺部,老年人多见,一部分病例会出现急性加重的过程,表现为原有肺部病变突然恶化和致死性的呼吸衰竭,并出现新的肺部阴影和弥漫性肺泡病理改变。特发性肺纤维化急性加重（AEIPF）可发生于接受肺切除术后的原发性肺癌患者,起病通常呈急性或亚急性过程,病因尚不明确,通常认为与不明原因的肺损伤相关,起病隐匿,病情进展迅速,病死率高,而且在临床缺乏常规的预防和治疗措施,成为困扰临床医生的难题。本文就肺癌术后特发性肺纤维化急性加重的病因、发生的危险因素、预测指标、预防、治疗、预后等方面做一系统综述。     

Emerging drugs for idiopathic pulmonary fibrosis

Pulmonary fibrosis is often the end stage of chronic, persistent, low-level lung injury, either of known or unknown cause. The most severe form of pulmonary fibrosis is idiopathic pulmonary fibrosis (IPF), a disease process of unknown aetiology and one that often leads to respiratory failure and death. At present there are no proven or effective drug therapies for IPF. Recent advances in understanding of disease pathogenesis have focused attention on drug targeting of fibrogenic pathways, as opposed to traditional anti-inflammatory approaches. In this report, the present status of drug development of a number of emerging antifibrotic strategies and agents that may prove more effective in the therapy of this progressive, debilitating and fatal disease are reviewed.     

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.