Emerging drugs for cystic fibrosis

Introduction: Cystic fibrosis is an autosomal recessive disease, which is the result of a genetic defect in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. Pulmonary disease accounts for over 90% of the morbidity and mortality associated with the disease. Conventionally, CF treatment has focused on symptomatic therapy.

Areas covered: In the past, the emphasis for the development of CF therapeutics has previously been on addressing complications of the manifestations rather than on the underlying disease process. However, in the past few decades there has been a paradigm shift with new attention on the underlying biological mechanisms and therapies targeted at curing the disease rather than simply controlling it. This review summarizes the current CF therapeutics pipeline. These developing therapies include CFTR gene therapy, CFTR pharmacotherapeutics, osmotically active agents and anti-inflammatory therapies, as well as novel inhaled antibiotics.

Expert opinion: The CF therapeutics pipeline currently holds great promise both for novel therapies directly targeting the underlying biological mechanisms of CFTR dysfunction and new symptomatic therapies. While CFTR-directed therapy has the highest potential to improve patients' outcome, it is important to continue to develop better treatment options for all aspects of CF lung disease.     

TGFβ as a therapeutic target in cystic fibrosis

Introduction: Cystic fibrosis (CF) is a genetic disease characterized by progressive lung disease. Most CF therapies focus on treating secondary pulmonary complications rather than addressing the underlying processes inducing airway remodeling and ineffective response to infection. Transforming growth factor beta (TGFβ) is a cytokine involved in fibrosis, inflammation, and injury response as well as a genetic modifier and biomarker of CF lung disease. Targeting the TGFβ pathway has been pursued in other diseases, but the mechanism of TGFβ effects in CF is less well understood.

Areas covered: In this review, we discuss CF lung disease pathogenesis with a focus on potential links to TGFβ. TGFβ signaling in lung health and disease is reviewed. Recent studies investigating TGFβ’s impact in CF airway epithelial cells are highlighted. Finally, an overview of potential therapies to target TGFβ signaling relevant to CF are addressed.

Expert opinion: The broad impact of TGFβ signaling on numerous cellular processes in homeostasis and disease is both a strength and a challenge to developing TGFβ dependent therapeutics in CF. We discuss the challenges inherent in developing TGFβ-targeted therapy, identifying appropriate patient populations, and questions regarding the timing of treatment. Future directions for research into TGFβ focused therapeutics are discussed.     

F508del-cystic fibrosis transmembrane regulator correctors for treatment of cystic fibrosis: a patent review

Introduction: Cystic fibrosis (CF) is an autosomal recessive genetic disease caused by malfunction of CF transmembrane regulator (CFTR). The deletion of a phenylalanine at residue 508 (F508del) is the most common mutation that causes cellular processing, chloride channel gating and protein stability defects in CFTR. Pharmacological modulators of F508del-CFTR, aimed at correcting the cellular processing defect (correctors) and the gating defect (potentiators) in CFTR protein, are regarded as promising therapeutic agents for CF disease. Endeavors in searching F508del-CFTR modulators have shown encouraging results, with several small-molecule compounds having entered clinical trials or even represented clinical options.

Areas covered: This review covers the discovery of F508del-CFTR correctors described in both patents (2005 – present) and scientific literatures.

Expert opinion: Cyclopropane carboxamide derivatives of CFTR correctors continue to dominate in this area, among which lumacaftor (a NBD1-MSD1/2 interface stabilizer) is the most promising compound and is now under the priority review by US FDA. However, the abrogation effect of ivacaftor (potentiator) on lumacaftor suggests the requirement of discovering new correctors and potentiators that can cooperate well. Integration screening for simultaneously identifying combinations of correctors (particularly NBD1 stabilizer) and potentiators should provide an alternative strategy. A recently reported natural product fraction library may be useful for the integration screening.     

Novel therapeutic approaches for pulmonary fibrosis

Pulmonary fibrosis represents the end stage of a number of heterogeneous conditions and is, to a greater or lesser degree, the hallmark of the interstitial lung diseases. It is characterized by the excessive deposition of extracellular matrix proteins within the pulmonary interstitium leading to the obliteration of functional alveolar units and in many cases, respiratory failure. While a small number of interstitial lung diseases have known aetiologies, most are idiopathic in nature, and of these, idiopathic pulmonary fibrosis is the most common and carries with it an appalling prognosis - median survival from the time of diagnosis is less than 3 years. This reflects the lack of any effective therapy to modify the course of the disease, which in turn is indicative of our incomplete understanding of the pathogenesis of this condition. Current prevailing hypotheses focus on dysregulated epithelial-mesenchymal interactions promoting a cycle of continued epithelial cell injury and fibroblast activation leading to progressive fibrosis. However, it is likely that multiple abnormalities in a myriad of biological pathways affecting inflammation and wound repair - including matrix regulation, epithelial reconstitution, the coagulation cascade, neovascularization and antioxidant pathways - modulate this defective crosstalk and promote fibrogenesis. This review aims to offer a pathogenetic rationale behind current therapies, briefly outlining previous and ongoing clinical trials, but will focus on recent and exciting advancements in our understanding of the pathogenesis of idiopathic pulmonary fibrosis, which may ultimately lead to the development of novel and effective therapeutic interventions for this devastating condition.     

Deciphering the toxicological role of Porphyromonas gingivalis derived endotoxins in liver diseases

Periodontitis is a most prevalent and infectious multifactorial inflammatory disease and is characterized by the progressive destruction of the tooth-supporting tissues. Porphyromonas gingivalis, a Gram‑negative oral anaerobe, mainly causes periodontitis and it is one of the most important risk factors responsible for aggravation of existing systemic diseases. Several experimental and clinical studies have shown the positive association between periodontitis and different forms of liver disease. Periodontal diseases increase the prevalence of non-alcoholic fatty liver diseases and cirrhosis. Infected periodontium and pathogens in the periodontal microenvironments release pathogen-associated molecular patterns such as peptidoglycan, lipopolysaccharides, gingipain, fimbria, bacterial DNA, etc, and damage-associated molecular patterns such as interleukins-1α, β, − 8, and galectin-3, etc. These virulence factors and cytokines enter the bloodstream, disseminate into the whole body, and induce a variety of systemic pathological effects, including liver diseases (steatosis and fibrosis). Maintaining oral hygiene by scaling and root planning significantly improves liver damage in patients with periodontitis. Dentists and physicians should have more awareness in understanding the bidirectional nature of the relationship between oral and systemic diseases. Importantly, periodontitis condition aggravates simple fatty liver into fibrotic disease and therefore, the aim of this review is to understand the possible link between periodontitis and liver diseases.     

特发性肺纤维化的发病机制及药物治疗研究进展

特发性肺纤维化是一种以两肺间质纤维化伴蜂窝状改变为特征的疾病,其发病率及死亡率逐年增高,且生存期较短,愈后极差,几乎与恶性肿瘤无异。因此,特发性肺纤维化发病机制和治疗也成为国际医学界的研究热点。本文就其病发机制和药物治疗研究进展进行了综述,为今后的进一步研究提供参考。     

Early life exposure to environmental tobacco smoke alters immune response to asbestos via a shift in inflammatory phenotype resulting in increased disease development

Asbestos in combination with tobacco smoke exposure reportedly leads to more severe physiological consequences than asbestos alone; limited data also show an increased disease risk due to environmental tobacco smoke (ETS) exposure. Environmental influences during gestation and early lung development can result in physiological changes that alter risk for disease development throughout an individual’s lifetime. Therefore, maternal lifestyle may impact the ability of offspring to subsequently respond to environmental insults and alter overall disease susceptibility. In this study, we examined the effects of exposure to ETS in utero and during early postnatal development on asbestos-related inflammation and disease in adulthood. ETS exposure in utero appeared to shift inflammation towards a Th2 phenotype, via suppression of Th1 inflammatory cytokine production. This effect was further pronounced in mice exposed to ETS in utero and during early postnatal development. In utero ETS exposure led to increased collagen deposition, a marker of fibrotic disease, when the offspring was later exposed to asbestos, which was further increased with additional ETS exposure during early postnatal development. These data suggest that ETS exposure in utero alters the immune responses and leads to greater disease development after asbestos exposure, which is further exacerbated when exposure to ETS continues during early postnatal development.     

PPAR-γ对肝纤维化相关信号转导途径的影响

肝纤维化是慢性肝病最重要的病理特征,其关键因素为肝星状细胞的活化使肝脏内纤维性结缔组织异常增生。过化物酶体增殖物激活受体（peroxisome proliferater-activated receptor-gamma,PPAR-γ）在肝星状细胞由静止表型向活化表型的转化中起重要作用,本文以近期研究中引人注目的肝纤维化的信号通路为重点,探讨PPAR-γ对肝纤维化信号通路的影响。     

TRPM7在心脏疾病中的研究进展

TRPM7（Transient receptor potential cation channel subfamily M member 7）是一种具有离子通道与蛋白激酶活性的双功能膜蛋白，在组织中广泛表达，参与多种细胞功能。近年来，大量研究表明TRPM7不仅在生理过程中发挥重要作用，而且在各种心脏疾病的发生和发展过程中起着关键性作用。因此，本综述分析了TRPM7在多种心脏疾病中(包括心肌纤维化，缺血性心脏病和糖尿病性心脏病)的作用，以了解其在疾病病理生理和发病机制中的潜在作用。     

Treatment of scleroderma: an update

The goal of this article is to update the reader and focus on novel therapies and clinical trials published since our last review [6]. Evidence suggests that drug intervention should target one or all of three biological processes: vascular disease, autommunity and tissue fibrosis. Efforts should be made to classify the subtype of scleroderma, to determine the activity of the disease process and the degree of specific organ involvement before specific treatment decisions are made. Cyclophosphamide in fibrosing alveolitis, intravenous prostaglandins and other vasodilators for the vascular disease, endothelin-1 inhibition in pulmonary hypertension and immunosuppressive therapy for early inflammatory disease, all appear to have benefit. Several agents used in vitro and in animal models of fibrosis also show promise including anti-transforming growth factor-β, the statins and anti-integrins. More experience in well-designed clinical trials is needed to define the role of these agents in treating scleroderma.     

Asbestos-associated mesothelial cell autoantibodies promote collagen deposition in vitro

Abstract

Fibrosis, characterized by excessive collagen protein deposition, is a progressive disease that can fatally inhibit organ function. Prolonged exposure to pathogens or environmental toxicants such as asbestos can lead to chronic inflammatory responses associated with fibrosis. Significant exposure to amphibole asbestos has been reported in and around Libby, Montana due to local mining of asbestos-contaminated vermiculite. These exposures have been implicated in a unique disease etiology characterized predominantly by pleural disorders, including fibrosis. We recently reported the discovery of mesothelial cell autoantibodies (MCAAs) in the sera of Libby residents and demonstrated a positive and significant correlation with pleural disease; however, a mechanistic link was not determined. Here we demonstrate that MCAAs induce pleural mesothelial cells to produce a collagen matrix but do not affect production of the pro-inflammatory cytokine tumor growth factor-β. While autoantibodies commonly induce a pro-fibrotic state by inducing epithelial–mesenchymal transition (EMT) of target cells, we found no evidence supporting EMT in cells exposed to MCAA positive human sera. Although implicated in other models of pulmonary fibrosis, activity of the protein SPARC (secreted protein, acidic and rich in cysteine) did not affect MCAA-induced collagen deposition. However, matrix formation was dependent on matrix metalloproteinase (MMP) activity, and we noted increased expression of MMP-8 and -9 in supernatants of mesothelial cells incubated with MCAA positive sera compared to control. These data suggest a mechanism by which MCAA binding leads to increased collagen deposition through altering MMP expression and provides an important mechanistic link between MCAAs and asbestos-related, autoimmune-induced pleural fibrosis.     

肺纤维化大鼠肺组织中肿瘤坏死因子-α受体表达的研究

目的探讨肿瘤坏死因子-α的受体(即TNFR1、TNFR2)在肺纤维化发病中的作用。方法 90只雄性Wistar大鼠。随机分为对照组、疾病模型组和甲泼尼龙治疗组,对照组给予生理盐水而模型组和治疗组给予博来霉素(5 mg/kg)一次性气管内注入,对照组和模型组于造模当天腹腔注射生理盐水(0.3 mL/只)以后每天1次,治疗组于造模当天腹腔注射甲泼尼龙(15 mg/kg)以后每天1次,后于第1、3、7、14、21、28天处死各组大鼠各5只,用免疫组织化学法观察肺组织中TNFR1、TNFR2的动态表达和变化,用碱水解法测肺组织中羟脯氨酸的含量。结果①肺组织中模型组TNFR1、TNFR2较对照组为强表达,尤其TNFR1高度表达,和对照组比较差异有统计学意义(P<0.05);而治疗组为弱表达,和模型组比较差异有统计学意义(P<0.05),但仍高于对照组,差异有统计学意义(P<0.05)。②各时间点模型组肺组织羟脯氨酸(HYP)含量较对照组明显升高,差异有统计学意义(P<0.05);而治疗组HYP含量有所下降和模型组比较差异有统计学意义(P<0.05),但仍高于对照组,且差异有统计学意义(P<0.05)。结论肺纤维化的发生的机制可能与TNFR1、TNFR2的过度表达有关,并依其表达水平可以推断疾病的进程。     

肺纤维化模型研究进展

肺纤维化（pulmonary fibrosis,PF）是一种严重的肺间质疾病,由于缺乏有效的药物治疗,其预后不良。这使得新的治疗药物的研究迫在眉睫,而建立良好的肺纤维化模型是进行药物研究的基础。本文通过整理和比较肺纤维化体内、体外多种模型的建立方法,以期为肺纤维化的药物研究提供良好的实验基础。     

Inhaled phosphodiesterase type 5 inhibitors for cystic fibrosis: a new therapy for systemic disease?

Cystic fibrosis is a rare disease characterized by abnormalities in chloride and sodium transmembrane transportation due to various mutations in the cystic fibrosis transmembrane regulator (CFTR) gene, F508del being the most commonly found. Corrective therapies for this defect are currently under investigation and PDE5 inhibitors such as sildenafil or vardenafil were found to improve CFTR activity in vitro as well as in vivo. This paper evaluates a study investigating the effects of inhaled PDE5 inhibitors in an animal model of F508del cystic fibrosis, demonstrating that in this new formulation, such compounds are also able to improve CFTR function. Such results support the further development of this therapy for a systemic disease such as cystic fibrosis, provided several issues are addressed.     

Efficacy and adverse effects of drugs used to treat adult cystic fibrosis

Introduction: Cystic fibrosis (CF) is an autosomal recessive disease and is the most commonly seen monogenetic disease in Caucasians. The disease has various manifestations resulting from the abnormal thick secretions, most common being chronic lung infection and airway obstruction. Many new promising drugs have appeared on the horizon over the years. This review here is an attempt to bring together the various treatments being used to prolong and enhance the quality of life of CF patients.

Areas covered: A literature review of published as well as ongoing clinical trials, meta-analysis and systematic reviews regarding the drugs used in CF management was carried out using PubMed and Ovid databases.

Expert opinion: New concepts have been formed and some positive results in this direction have already led to the approval of cystic fibrosis transmembrane conductance regulator potentiator drug. Gene therapy and stem cell therapy are under development. The current therapies such as dornase alfa and pancreatic enzymes targeting the symptoms continue to evolve as they play an important complementary role. Development of new simple and cost-effective markers, which help assess the efficacy and safety of these constantly emerging new drugs, is also being investigated.     

Pharmacotherapy of systemic sclerosis

Importance of the field: Systemic sclerosis (SSc) is an uncommon autoimmune disease with variable degrees of fibroproliferation in blood vessels and certain organs of the body. There is currently no cure. The purpose of this article is to review the current literature regarding pathogenesis and treatment of complications of SSc.

Areas covered in this review: All available articles regarding research related to SSc pathogenesis and treatment listed in the PubMed database were searched; relevant articles were then reviewed and used as sources of information for this review.

What the reader will gain: This review attempts to highlight for the reader some current thought regarding mechanisms of SSc pathogenesis and how autoimmunity relates to vascular changes and fibrogenesis of the disease, as well as providing a review of results of completed clinical trials and current ongoing clinical trials that address organ-specific or global therapies for this disease. This can aid physicians who provide medical care for patients with SSc.

Take home message: SSc is a complex autoimmune disease, the pathogenesis of which, although not completely understood, is under active study; new insights into pathogenesis are continually being discovered. Although there is no effective disease-modifying treatment for patients with SSc, quality of life, morbidity and mortality can be improved by using targeted therapy directed at affecting the consequences of damage to lungs, blood vessels, kidneys and the gastrointestinal tract. Innovative approaches to treating SSc are under intense investigation.     

慢性肝病患者纤维化指标观察

目的观察慢性肝病患者的血清纤维化指标。方法对收治的住院或门诊慢性乙型肝炎或肝硬化患者78例作为试验组,门诊常规非肝病健康人群30例作为对照组,分别进行统计学研究。结果根据肝穿病理组织学检查结果两组比较差异具有统计学意义（P〈0.01）。结论观察慢性肝病患者的血清纤维化指标对诊断肝纤维化,对判断慢性肝病的活动、发展趋势、治疗及预后均具有较高价值。     

Pirfenidone; can it be a new horizon for the treatment of pulmonary fibrosis in mustard gas-intoxicated patients?

Sulfur mustard is an alkylating substance still regarded as a threat in chemical warfare and terrorism. Lung parenchymal damage occurs in the most severe inhalational exposures. It accompanies an increased risk of respiratory tract carcinomas and chronic respiratory sequelae including chronic bronchitis, bronchiectasis, pulmonary fibrosis, interstitial lung disease, emphysema, and bronchiolitis obliterans. Pirfenidone is an antifibrotic with anti-inflammatory and anti hydroxyl radical activities which stabilizes pulmonary function in idiopathic pulmonary fibrosis patients. It can be suggested in chronically exposed soldiers or workers with signs and symptoms of pulmonary fibrosis to improve their quality of life and even prognosis.