Molecular mechanisms of and possible treatment strategies for idiopathic pulmonary fibrosis

Pulmonary fibrosis is characterized by lung inflammation and abnormal tissue repair, resulting in the replacement of normal functional tissue with an abnormal accumulation of fibroblasts and deposition of collagen in the lung. This process involves cellular interactions via a complex cytokine-signaling mechanism and heightened collagen gene expression, ultimately resulting in its abnormal collagen deposition in the lung. Our current understanding of the pathogenesis of pulmonary fibrosis suggests that in addition to inflammatory cells, the fibroblast and signaling events that mediate fibroblast proliferation and myofibroblasts, play important roles in the diverse processes that constitute fibrosis. Increasing knowledge of cytokine biology, cytokine-signaling and cell matrix interactions have shed some light on the genesis of pulmonary fibrosis; however, the importance of inflammation in pulmonary fibrosis remains controversial. This remains true because the inflammatory component is variable at the time of diagnosis, and the most potent anti-inflammatory drugs that have been widely used in the treatment of pulmonary fibrosis do not seem to interfere with the fibrotic disease progression. Pulmonary fibrosis is a highly lethal disorder, which continues to pose major clinical challenges because an effective therapeutic regimen is yet to be determined. This review summarizes recent progress in understanding the molecular mechanisms of pulmonary fibrosis, and includes a more detailed discussion of the potential points of therapeutic attack in pulmonary fibrosis. In addition, a detailed discussion is presented regarding each of the potential therapies which have emerged from the animal models of pulmonary fibrosis, and which have been developed through advances in cellular and molecular biology.     

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.     

反义核酸技术在受胶原基因表达调控的肝纤维化研究中的应用

肝纤维化是慢性肝损伤的修复反应,以胶原为主的细胞外基质（ECM）在肝内大量沉积的病理过程。其形成机制较为复杂,各种细胞因子彼此相互作用,形成细胞因子网络,共同调控肝纤维化的发生、发展。抗肝纤维化治疗策略主要包括调控HSC活化增殖或促其凋亡、抑制胶原合成或促其降解、细胞因子治疗和间充质干细胞治疗等。反义核酸技术是一种发展迅速并极富应用前景的基因控制技术。它是利用DNA或RNA分子通过Watson Crick碱基配对原则与目的基因的mRNA互补结合,通过各种机制使其降解或抑制其编码蛋白的翻译,从而抑制目的基因的表达,主要包括反义寡核苷酸技术、RNA干扰技术和三股螺旋结构寡核苷酸技术。本文综述了应用反义核酸技术调控相关基因的表达来防治肝纤维化的研究现状。     

小窝蛋白-1与特发性肺纤维化

小窝蛋白作为小窝膜内的支架蛋白,能够组织和浓缩特异性的脂质,修饰信号转导分子以及负性调控许多信号转导通路和生物过程。生物体内小窝蛋白表达异常可引起疾病,特发性肺纤维化就是其中一种。大量研究表明,小窝蛋白-1在特发性肺纤维化发病过程中表达明显下调,大大降低了其对多条信号传导通路如TGF-β/SMAD、ERK/MAPK、JNK/MAPK和PKC等的负性调控作用,进而导致肺泡上皮细胞损伤、成纤维细胞增殖及表型转化、细胞外基质(ECM)重塑,加速了肺纤维化发病进程。因此该文就小窝蛋白-1在特发性肺纤维化中的作用进行了综述。     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Targeting matrix metalloproteases to improve cutaneous wound healing

Wound repair is a physiological event in which tissue injury initiates a repair process leading to restoration of structure and function of the tissue. Cutaneous wound repair can be divided into a series of overlapping phases including formation of fibrin clot, inflammatory response, granulation tissue formation incorporating re-epithelialisation and angiogenesis and finally, matrix formation and remodelling. Matrix metalloproteases (MMPs) are a family of neutral proteases that play a vital role throughout the entire wound healing process. They regulate inflammation, degrade the extracellular matrix (ECM) to facilitate the migration of cells and remodel the new ECM. However, excessive MMP activity contributes to the development of chronic wounds. Selective control of MMP activity may prove to be a valuable therapeutic approach to promote healing of chronic ulcers. Recent evidence indicates that the anticoagulant, activated protein C may be useful in the treatment of non-healing wounds by preventing excessive protease activity through inhibition of inflammation and selectively increasing MMP-2 activity to enhance angiogenesis and re-epithelialisation.     

Adipokines and liver fibrosis

Liver fibrosis involves different cell types, and should be regarded as a "wound healing" response that occurres in conditions of chronic liver injury and is characterized by inflammation, activation of matrix-producing cells, matrix deposition and remodeling, and epithelial cell regeneration or an attempt thereof. Liver damage may be caused by several agents or conditions, resulting in different degrees and types of tissue inflammation and in activation of matrix-producing cells, such as the hepatic stellate cells (HSC). HSC undergo a phenotypic transition (known as "activation") to myofibroblast-like cells that synthesize different extracellular matrix components. Obesity is associated with the development of NASH, and has been indicated as an independent factor for the progression to fibrosis. In liver diseases, the biologic actions of the adipokines, such as leptin, adiponectin and resistin, released by adipocytes or locally produced by liver and/or inflammatory cells, may contribute to clarify the mechanisms of progression in NASH. The clinical and experimental findings accumulating on this class of molecules could represent the basis to devise a better management strategy for the patients with chronic liver disease.     

Growth factor regulation and manipulation in wound repair: to scar or not to scar,that is the question

The process of tissue repair following injury is in the large part mediated by secreted growth factors which, in an autocrine or paracrine fashion, stimulate immune and mesenchymal cells at the site of injury. The complex process of replacing damaged tissue with newly formed tissue involves components of the blood, coagulation, immune and mesenchymal systems as well as cytokines, chemokines, metalloproteinases and growth factors. This review will focus on growth factors as the controllers of this process and includes members of the transforming growth factor (TGF), platelet derived growth factor (PDGF), fibroblast growth factor (FGF), connective tissue derived growth factor (CTGF) and insulin-like growth factor-I (IGF-I) families of growth factors. These growth factors stimulate re-epithelialisation, angiogenesis, extracellular matrix (ECM) formation and cell proliferation each of which plays a role in tissue replacement and restoration of tissue function following injury. Normal wound healing frequently involves the formation of scar tissue, including increased mesenchymal cell proliferation and excessive production of ECM proteins. While scar tissue rapidly and effectively closes wounds, it leaves visually apparent tissue structure changes and may reduce the function of the tissue leading to compromised organ function. Growth factors, the conductors of these processes, are targets for therapeutic manipulation of wound healing and scar formation. Recent patents involving growth factors may be implicated in the treatment of wound healing following tissue injury. Enhanced growth factor activity may be beneficial to increase the rate of wound healing in chronic non-healing wounds, whereas reduction of growth factor presence or activity may reduce scar formation in the skin and internal organs, which may be particularly relevant where scar formation is associated with pathologic loss of life sustaining organ function.     

Current and emerging drugs for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a chronic, progressive and often fatal form of interstitial lung disease. It is characterized by injury with loss of lung epithelial cells and abnormal tissue repair, resulting in abnormal accumulation of fibroblasts and myofibroblasts, deposition of extracellular matrix and distortion of lung architecture, leading to respiratory failure. This lethal lung disorder continues to pose major clinical challenges as an effective therapeutic regimen has yet to be developed. In this report, therapeutic strategies are reviewed, including the use of antifibrotic agents, inhibition of cytokines, leukotrienes and cytokines receptors, and molecular targeting of specific signaling pathways during fibrotic processes and angiogenesis. This article examines the body of evidence supporting present therapies and reviews the newer agents being tested in patients with idiopathic pulmonary fibrosis.     

Current and emerging drugs for idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis is a chronic, progressive and often fatal form of interstitial lung disease. It is characterized by injury with loss of lung epithelial cells and abnormal tissue repair, resulting in abnormal accumulation of fibroblasts and myofibroblasts, deposition of extracellular matrix and distortion of lung architecture, leading to respiratory failure. This lethal lung disorder continues to pose major clinical challenges as an effective therapeutic regimen has yet to be developed. In this report, therapeutic strategies are reviewed, including the use of antifibrotic agents, inhibition of cytokines, leukotrienes and cytokines receptors, and molecular targeting of specific signaling pathways during fibrotic processes and angiogenesis. This article examines the body of evidence supporting present therapies and reviews the newer agents being tested in patients with idiopathic pulmonary fibrosis.     

肝纤维化与细胞因子的关系

肝纤维化是肝损伤后的修复机制 ,肝星形细胞的过度激活是肝纤维化的中心事件 ,并最终导致大量细胞外基质的合成。主要由激活枯否细胞分泌的细胞因子作为重要的影响因素 ,刺激或抑制肝纤维化的发生发展 ;肝纤维化和细胞因子关系密切。本文就肝纤维化关系密切的及有望应用于肝纤维化治疗的细胞因子作一综述     

The innate immune system,toll-like receptors and dermal wound healing: A review

Wound healing is a complex physiological process comprised of discrete but inter-related and overlapping stages, requiring exact timing and regulation to successfully progress, yet occurs spontaneously in response to injury. It is characterised by four phases, coagulation, inflammation, proliferation and remodelling. Each phase is predominated by particular cell types, cytokines and chemokines. The innate immune system represents the first line of defence against invading microorganisms. It is entirely encoded with the genome, and comprised of a cellular response with specificity provided by pattern recognition receptors (PRRs) such as toll-like receptors (TLRs). TLRs are activated by exogenous microbial pathogen associated molecular patterns (PAMPs), initiating an immune response through the production of pro-inflammatory cytokines and further specialist immune cell recruitment. TLRs are also activated by endogenous molecular patterns termed damage associated molecular patterns (DAMPs). These ligands, usually shielded from the immune system, act as alarm signals alerting the immune system to damage and facilitate the normal wound healing process. TLRs are expressed by cells essential to wound healing such as keratinocytes and fibroblasts, however the specific role of TLRs in this process remains controversial. This article reviews the current knowledge on the potential role of TLRs in dermal wound healing where inflammation arising from pathogenic activation of these receptors appears to play a role in chronic ulceration associated with diabetes, scar hypertrophy and skin fibrosis.     

Targeting aberrant TGF-beta signaling in pre-clinical models of cancer

The TGF-beta signaling pathway is central to the control of diverse biological processes including cellular proliferation, cell survival, apoptosis, extracellular matrix deposition/remodeling, migration, invasion and immune regulation/inflammation. Given the pleiotropic effects of this cytokine, it comes as no surprise that numerous pathological conditions are associated with alterations in the TGF-beta pathway, including chronic fibrosis, airway remodeling (asthma), cardiovascular disease and cancer. Thus, there are increasing efforts to develop reagents and therapeutic strategies to impair TGF-beta signaling. Here we review several classes of inhibitors, including knock-down strategies aimed at signaling components of the TGF-beta pathway, TGF-beta neutralizing antibodies, TGF-beta receptor extracellular domains that function as ligand traps and small molecule kinase inhibitors. Strategies with potential for application as anti-cancer therapeutics that have been evaluated in pre-clinical animal models will be discussed. TGF-beta action is complex, shifting from a tumor suppressor to a promoter of tumor cell invasion and metastasis in several types of cancer. This raises important issues regarding not only the status of the TGF-beta pathway in the individual patient but also the precise stage during disease progression that such inhibitors should be employed. Potential consequences of targeting the TGF-beta pathway will also be considered.     

Antioxidant and anti-inflammatory potential of curcumin accelerated the cutaneous wound healing in streptozotocin-induced diabetic rats

Prolonged inflammation and increased oxidative stress impairs healing in diabetics and application of curcumin, a well known antioxidant and anti-inflammatory agent, could be an important strategy in improving impaired healing in diabetics. So, the present study was conducted to evaluate the cutaneous wound healing potential of topically applied curcumin in diabetic rats. Open excision skin wound was created in streptozotocin induced diabetic rats and wounded rats were divided into three groups; i) control, ii) gel-treated and iii) curcumin-treated. Pluronic F-127 gel (25%) and curcumin (0.3%) in pluronic gel were topically applied in the gel- and curcumin-treated groups, respectively, once daily for 19 days. Curcumin application increased the wound contraction and decreased the expressions of inflammatory cytokines/enzymes i.e. tumor necrosis factor-alpha, interleukin (IL)-1beta and matrix metalloproteinase-9. Curcumin also increased the levels of anti-inflammatory cytokine i.e. IL-10 and antioxidant enzymes i.e. superoxide dismutase, catalase and glutathione peroxidase. Histopathologically, the curcumin-treated wounds showed better granulation tissue dominated by marked fibroblast proliferation and collagen deposition, and wounds were covered by thick regenerated epithelial layer. These findings reveal that the anti-inflammatory and antioxidant potential of curcumin caused faster and better wound healing in diabetic rats and curcumin could be an additional novel therapeutic agent in the management of impaired wound healing in diabetics.     

TGF-β对创伤愈合与瘢痕形成的影响及中药的干预作用

目的对近年来转化生长因子β(transforming growth factorβ,TGF-β)在创伤愈合和瘢痕形成过程中的作用及中药对其的干预作用做以综述。方法查阅大量国内外文献,分析、总结TGF-β在创伤愈合和瘢痕形成过程中的研究现状和研究前景。结果 TGF-β在调节细胞增殖、分化、迁移、黏附及细胞外基质形成、胚胎发育、骨的重建等方面发挥重要作用。TGF-β在创伤愈合和瘢痕形成过程中是关键的活性分子,TGF-β的3种亚型在创伤愈合过程中存在时间和空间上的差异性,且功能各异。中药由于其成分复杂,在创伤修复及瘢痕形成过程中显示不同的作用特点,对TGF-β的干预作用也呈现不同特点。结论 TGF-β在创伤愈合和瘢痕形成过程中发挥着重要的作用,具体作用机制有待进一步阐明。因此探讨TGF-β在创伤愈合和瘢痕形成过程中的作用机制及中药对其的干预作用具有重要意义。     

Nitric oxide： a newly discovered function on wound healing

Wound healing impairment represents a particularly challenging clinical problem to which no efficacious treatment regimens currently exist. The factors ensuring appropriate intercellular communication during wound repair are not completely understood. Although protein-type mediators are well-established players in this process, emerging evidence from both animal and human studies indicates that nitric oxide (NO) plays a key role in wound repair. The beneficial effects of NO on wound repair may be attributed to its functional influences on angiogenesis, inflammation, cell proliferation, matrix deposition, and remodeling. Recent findings from in vitro and in vivo studies of NO on wound repair are summarized in this review. The unveiled novel mechanisms support the use of NO-containing agents and/or NO synthase gene therapy as new therapeutic regimens for impaired wound healing.     

The role of cardiac fibroblasts in the transition from inflammation to fibrosis following myocardial infarction

Cardiac fibroblasts (CF) play a pivotal role in the repair and remodeling of the heart that occur following myocardial infarction (MI). The transition through the inflammatory, granulation and maturation phases of infarct healing is driven by cellular responses to local levels of cytokines, chemokines and growth factors that fluctuate in a temporal and spatial manner. In the acute inflammatory phase early after MI, CF contribute to the inflammatory milieu through increased secretion of proinflammatory cytokines and chemokines, and they promote extracellular matrix (ECM) degradation by increasing matrix metalloproteinase (MMP) expression and activity. In the granulation phase, CF migrate into the infarct zone, proliferate and produce MMPs and pro-angiogenic molecules to facilitate revascularization. Fibroblasts also undergo a phenotypic change to become myofibroblasts. In the maturation phase, inflammation is reduced by anti-inflammatory cytokines, and increased levels of profibrotic stimuli induce myofibroblasts to synthesize new ECM to form a scar. The scar is contracted through the mechanical force generated by myofibroblasts, preventing cardiac dilation. In this review we discuss the transition from myocardial inflammation to fibrosis with particular focus on how CF respond to alterations in proinflammatory and profibrotic signals. By furthering our understanding of these events, it is hoped that new therapeutic interventions will be developed that selectively reduce adverse myocardial remodeling post-MI, while sparing essential repair mechanisms.     

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.     

Role of inflammatory mediators in angiogenesis

The angiogenic process involves several cell types and mediators, which interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. Angiogenesis occurs in several physiological and pathological conditions, such as embryo development and wound healing, diabetic retinopathy and tumours. Inflammatory cells, namely monocytes/macrophages, T lymphocytes and neutrophils, fully participate in the angiogenic process by secreting cytokines that may affect endothelial cell (EC) functions, including EC proliferation, migration and activation. Angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. With regards to inflammatory cells and endothelium cross-talk, such balance is conceptually very similar to that of pro-inflammatory and anti-inflammatory mediators that modulate an appropriate inflammatory response. In this review we will mainly discuss the relevance of both physiological and pathological inflammatory processes in angiogenesis, with particular regards to microenvironmental contribution. We will also describe some of the most relevant pro-inflammatory cytokines in the modulation of the angiogenic process. Furthermore, we will concentrate on what has been recently reported about the mechanism by which some of these cytokines are induced during inflammation to promote a suitable microenvironment for angiogenesis and tumour progression. Pro-angiogenic cytokines, such as IL-1 and TNF, and anti-angiogenic cytokines such as IFN-gamma and IL-12, will be briefly described. We will try to provide a rationale for the use of both cytokines and cytokine blockades as novel potential pharmaceutical targets to modulate angiogenesis in chronic inflammation as well as in cancer.