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Annual Review of Medicine 2004Tissue injury evokes highly conserved, tightly regulated inflammatory responses and less well-understood host repair responses. Both inflammation and repair involve the... (Review)
Review
Tissue injury evokes highly conserved, tightly regulated inflammatory responses and less well-understood host repair responses. Both inflammation and repair involve the recruitment, activation, apoptosis, and eventual clearance of key effector cells. In this review, we propose the concept of pulmonary fibrosis as a dysregulated repair process that is perpetually "turned on" even though classical inflammatory pathways may be dampened or "switched off." Significant regional heterogeneity, with varied histopathological patterns of inflammation and fibrosis, has been observed in individual patients with idiopathic pulmonary fibrosis. We discuss environmental factors and host response factors, such as genetic susceptibility and age, that may influence these varied manifestations. Better understanding of the mechanisms of lung repair, which include alveolar reepithelialization, myofibroblast differentiation/activation, and apoptosis, should offer more effective therapeutic options for progressive pulmonary fibrosis.
Topics: Humans; Lung; Pulmonary Fibrosis
PubMed: 14746528
DOI: 10.1146/annurev.med.55.091902.103810 -
Expert Review of Respiratory Medicine May 2017Many forms of interstitial lung disease (ILD) can progress to extensive fibrosis and respiratory failure. Idiopathic pulmonary fibrosis (IPF), which generally has a poor... (Review)
Review
Many forms of interstitial lung disease (ILD) can progress to extensive fibrosis and respiratory failure. Idiopathic pulmonary fibrosis (IPF), which generally has a poor prognosis, has been thoroughly studied over the past two decades, and many important discoveries have been made that pertain to genetic predisposition, epidemiology, disease pathogenesis, diagnosis, and management. Additionally, non-IPF forms of ILD can have radiologic and histopathologic manifestations that mimic IPF, and making an accurate diagnosis is key to providing personalized medicine to patients with pulmonary fibrosis. Areas covered: This manuscript discusses current knowledge pertaining to the genetics, epidemiology, pathogenesis, and diagnosis of pulmonary fibrosis with an emphasis on IPF. The material upon which this discussion is based was obtained from various published texts and manuscripts identified via literature searching (e.g. PubMed). Expert commentary: Many genetic variants have been identified that are associated with risk of developing pulmonary fibrosis, and an improved understanding of the influence of both genomic and epigenomic factors in the development of pulmonary fibrosis is rapidly evolving. Because many forms of fibrosing ILD can have similar radiologic and histopathologic patterns yet have different responses to therapeutic interventions, making an accurate diagnosis of specific forms of pulmonary fibrosis is increasingly important.
Topics: Humans; Pulmonary Fibrosis
PubMed: 28345383
DOI: 10.1080/17476348.2017.1312346 -
Trends in Molecular Medicine Dec 2023Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange,... (Review)
Review
Pulmonary fibrosis (PF) encompasses a spectrum of chronic lung diseases that progressively impact the interstitium, resulting in compromised gas exchange, breathlessness, diminished quality of life (QoL), and ultimately respiratory failure and mortality. Various diseases can cause PF, with their underlying causes primarily affecting the lung interstitium, leading to their referral as interstitial lung diseases (ILDs). The current understanding is that PF arises from abnormal wound healing processes triggered by various factors specific to each disease, leading to excessive inflammation and fibrosis. While significant progress has been made in understanding the molecular mechanisms of PF, its pathogenesis remains elusive. This review provides an in-depth exploration of the latest insights into PF pathophysiology, diagnosis, treatment, and future perspectives.
Topics: Humans; Pulmonary Fibrosis; Quality of Life; Lung Diseases, Interstitial; Lung; Fibrosis; Clinical Decision-Making
PubMed: 37716906
DOI: 10.1016/j.molmed.2023.08.010 -
The Journal of Clinical Investigation Aug 2012Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need.... (Review)
Review
Pulmonary fibrosis occurs in a variety of clinical settings, constitutes a major cause of morbidity and mortality, and represents an enormous unmet medical need. However, the disease is heterogeneous, and the failure to accurately discern between forms of fibrosing lung diseases leads to inaccurate treatments. Pulmonary fibrosis occurring in the context of connective tissue diseases is often characterized by a distinct pattern of tissue pathology and may be amenable to immunosuppressive therapies. In contrast, idiopathic pulmonary fibrosis (IPF) is a progressive and lethal form of fibrosing lung disease that is recalcitrant to therapies that target the immune system. Although animal models of fibrosis imperfectly recapitulate IPF, they have yielded numerous targets for therapeutic intervention. Understanding the heterogeneity of these diseases and elucidating the final common pathways of fibrogenesis are critical for the development of efficacious therapies for severe fibrosing lung diseases.
Topics: Animals; Genetic Predisposition to Disease; Humans; Idiopathic Pulmonary Fibrosis; Mesoderm; Models, Biological; Pulmonary Alveoli; Pulmonary Fibrosis; Respiratory Mucosa
PubMed: 22850886
DOI: 10.1172/JCI60323 -
Lancet (London, England) Dec 2011Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic... (Review)
Review
Idiopathic pulmonary fibrosis is a devastating, age-related lung disease of unknown cause that has few treatment options. This disease was once thought to be a chronic inflammatory process, but current evidence indicates that the fibrotic response is driven by abnormally activated alveolar epithelial cells (AECs). These cells produce mediators that induce the formation of fibroblast and myofibroblast foci through the proliferation of resident mesenchymal cells, attraction of circulating fibrocytes, and stimulation of the epithelial to mesenchymal transition. The fibroblast and myofibroblast foci secrete excessive amounts of extracellular matrix, mainly collagens, resulting in scarring and destruction of the lung architecture. The mechanisms that link idiopathic pulmonary fibrosis with ageing and aberrant epithelial activation are unknown; evidence suggests that the abnormal recapitulation of developmental pathways and epigenetic changes have a role. In this Seminar, we review recent data on the clinical course, therapeutic options, and underlying mechanisms thought to be involved in the pathogenesis of idiopathic pulmonary fibrosis.
Topics: Humans; Idiopathic Pulmonary Fibrosis; Prognosis
PubMed: 21719092
DOI: 10.1016/S0140-6736(11)60052-4 -
International Journal of Molecular... Nov 2022Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary... (Review)
Review
Pulmonary fibrosis is a chronic progressive lung disease that steadily leads to lung architecture disruption and respiratory failure. The development of pulmonary fibrosis is mostly the result of previous acute lung inflammation, caused by a wide variety of etiological factors, not resolved over time and causing the deposition of fibrotic tissue in the lungs. Despite a long history of study and good coverage of the problem in the scientific literature, the effective therapeutic approaches for pulmonary fibrosis treatment are currently lacking. Thus, the study of the molecular mechanisms underlying the transition from acute lung inflammation to pulmonary fibrosis, and the search for new molecular markers and promising therapeutic targets to prevent pulmonary fibrosis development, remain highly relevant tasks. This review focuses on the etiology, pathogenesis, morphological characteristics and outcomes of acute lung inflammation as a precursor of pulmonary fibrosis; the pathomorphological changes in the lungs during fibrosis development; the known molecular mechanisms and key players of the signaling pathways mediating acute lung inflammation and pulmonary fibrosis, as well as the characteristics of the most common in vivo models of these processes. Moreover, the prognostic markers of acute lung injury severity and pulmonary fibrosis development as well as approved and potential therapeutic approaches suppressing the transition from acute lung inflammation to fibrosis are discussed.
Topics: Humans; Pulmonary Fibrosis; Prognosis; Lung; Pneumonia; Fibrosis; Inflammation
PubMed: 36499287
DOI: 10.3390/ijms232314959 -
Environmental Pollution (Barking, Essex... Apr 2023Exposure to ambient fine particulate matter (PM) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal...
Exposure to ambient fine particulate matter (PM) has been linked to a higher pulmonary fibrosis risk. Dysregulation of the epitranscriptome results in abnormal expression of mRNAs during fibrosis development. N4-acetylcytidine (ac4C) is one of the most frequent RNA epigenetic alterations, however, its function in PM-triggered fibrosis is yet unknown. In this study, lung epithelial and murine models were established and exposed to PM to analyze the function of ac4C alteration in pulmonary fibrosis and underlying mechanisms. Meanwhile, the expression levels of only known ac4C "writer" protein, N-acetyltransferase 10 (NAT10), were significantly induced in pulmonary epithelia, relative to the control. Subsequently, NAT10 enhanced the stability of transforming growth factor beta 1 (TGFB1) mRNA as well as protein levels. As an up-stream driver, TGFB1 accelerated EMT and fibrosis process. Inhibition of NAT10 significantly protected against pulmonary EMT and fibrosis driven by PM exposure, whereas TGFB1 overexpression reversed the protective effects of NAT10 inhibition. Thus, NAT10 accelerated PM-triggered pulmonary fibrosis via increasing TGFB1 mRNA stability in an ac4C-dependent manner. Our results reveal a pivotal role of NAT10-regulated mRNA ac4C acetylation in PM-triggered pulmonary fibrosis and uncover the potential epitranscriptional mechanism.
Topics: Animals; Mice; Lung; Particulate Matter; Pulmonary Fibrosis; RNA; RNA, Messenger
PubMed: 36731737
DOI: 10.1016/j.envpol.2023.121149 -
MMW Fortschritte Der Medizin Feb 2023
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The International Journal of... 2008Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the... (Review)
Review
Different animal models of pulmonary fibrosis have been developed to investigate potential therapies for idiopathic pulmonary fibrosis (IPF). The most common is the bleomycin model in rodents (mouse, rat and hamster). Over the years, numerous agents have been shown to inhibit fibrosis in this model. However, to date none of these compounds are used in the clinical management of IPF and none has shown a comparable antifibrotic effect in humans. We performed a systematic review of publications on drug efficacy studies in the bleomycin model to evaluate the value of this model regarding transferability to clinical use. Between 1980 and 2006 we identified 240 experimental studies describing beneficial antifibrotic compounds in the bleomycin model. 222 of those used a preventive regimen (drug given < or =7 days after last bleomycin application), only 13 were therapeutic trials (>7 days after last bleomycin application). In 5 studies we did not find enough details about the timing of drug application to allow inter-study comparison. It is critical to distinguish between drugs interfering with the inflammatory and early fibrogenic response from those preventing progression of fibrosis, the latter likely much more meaningful for clinical application. All potential antifibrotic compounds should be evaluated in the phase of established fibrosis rather than in the early period of bleomycin-induced inflammation for assessment of its antifibrotic properties. Further care should be taken in extrapolation of drugs successfully tested in the bleomycin model due to partial reversibility of bleomycin-induced fibrosis over time. The use of alternative and more robust animal models, which better reflect human IPF, is warranted.
Topics: Animals; Bleomycin; Clinical Trials as Topic; Disease Models, Animal; Humans; Pulmonary Fibrosis
PubMed: 17936056
DOI: 10.1016/j.biocel.2007.08.011 -
The New England Journal of Medicine Aug 2001Idiopathic pulmonary fibrosis is a rapidly progressive illness of unknown cause characterized by sequential acute lung injury with subsequent scarring and end-stage lung... (Review)
Review
Idiopathic pulmonary fibrosis is a rapidly progressive illness of unknown cause characterized by sequential acute lung injury with subsequent scarring and end-stage lung disease. Treatment at present remains largely supportive, with evidence that patients' satisfaction and survival may be improved by referral to centers specializing in the evaluation of interstitial lung diseases. Although no drug therapy has clearly been demonstrated to benefit patients with idiopathic pulmonary fibrosis, a number of novel investigational agents hold promise for future study. Given the poor prognosis associated with idiopathic pulmonary fibrosis, patients should be referred to regional centers of expertise for enrollment in therapeutic clinical trials or for lung transplantation.
Topics: Adjuvants, Immunologic; Anti-Inflammatory Agents; Disease Progression; Fibrinolytic Agents; Humans; Lung; Lung Transplantation; Pulmonary Fibrosis; Radiography; Steroids
PubMed: 11519507
DOI: 10.1056/NEJMra003200