Materiały źródłowe

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  Pulmonary fibrosis and architectural remodeling of tissues can severely disrupt lung function, often with fatal consequences. The etiology of pulmonary fibrotic diseases is varied, with an array of triggers including allergens, chemicals, radiation and environmental particles. However, the cause of one of the most common pulmonary fibrotic conditions, idiopathic pulmonary fibrosis (IPF), is still unclear. This review examines common mechanisms of pulmonary wound-healing responses following lung injury, and highlights the pathogenesis of some of the most widespread pulmonary fibrotic diseases. A three phase model of wound repair is reviewed that includes; (1) injury; (2) inflammation; and (3) repair. In most pulmonary fibrotic conditions dysregulation at one or more of these phases has been reported. Chronic inflammation can lead to an imbalance in the production of chemokines, cytokines, growth factors, and disrupt cellular recruitment. These changes coupled with excessive pro-fibrotic IL-13 and/or TGF1 production can turn a well-controlled healing response into a pathogenic fibrotic response. Endogenous regulatory mechanisms are discussed including novel areas of therapeutic intervention. Restoring homeostasis to these dysregulated healing responses, or simply neutralizing the key pro-fibrotic mediators may prevent or slow the progression of pulmonary fibrosis.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  Following injury it is paramount that tissue architecture is restored to regain normal organ function. Acute inflammatory responses that result from infection or injury can disrupt epithelial and endothelial integrity leading to edema, the recruitment of leukocytes and angiogenesis. The resolution of inflammation through apoptotic and phagocytic pathways often leaves minimal damage and restores normal tissue architecture. However, common to most fibrotic conditions is the presence of a persistent irritant, which can be known agents, such as allergens, toxic chemicals, radiation, or other persistent irritants or unknown factors that trigger idiopathic pulmonary fibrosis (IPF). Indeed, a dysregulated healing response can gradually evolve into a pathogenic fibrotic response when important checkpoints are missed and inflammation becomes unrelenting.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  A wound-healing response is often described as having three distinct phasesinjury, inflammation and repair. Although not all pulmonary fibrotic conditions follow this simple paradigm, it has been a useful model to elucidate the common and divergent mechanisms of pulmonary fibrosis. […] Injury caused by autoimmune or allergic reactions, environmental particulates, infection or mechanical damage often results in the disruption of normal tissue architecture, initiating a healing response. Inflammation following insult, can also contribute to cellular damage and tissue destruction. Damaged epithelial and endothelial cells must be replaced to maintain barrier function and integrity and prevent blood loss, respectively. Acute damage to endothelial cells leads to the release of inflammatory mediators and initiation of an anti-fibrinolytic coagulation cascade, temporarily plugging the damaged vessel with a platelet and fibrin-rich clot.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  The nature of the inflammatory response dramatically influences resident tissue cells and the ensuing inflammatory cells. Inflammatory cells themselves also propagate further inflammation through the secretion of chemokines, cytokines, and growth factors. […] IL-4, the archetypal type-2 cytokine, has been firmly established as a pro-fibrotic cytokine and is elevated in IPF, cryptogenic fibrosing alveolitis, radiation-induced pneumonitis and pulmonary fibrosis as well as liver fibrosis following infection with Schistomsoma mansoni. […] IL-13 shares many properties with IL-4, due to common receptor subunits (IL-4R), signal transduction pathways and transcription factors (STAT-6). However, recent animal studies have identified IL-4R- and STAT-6-independent IL-13-associated responses, which may involve IL-13 signaling through IL-13R2.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  The nature of the insult or causative agent often dictates the character of the ensuing inflammatory response. For example, exogenous stimuli like pathogen-associated molecular patterns (PAMPs) are recognized by pathogen recognition receptors, such as toll-like receptors and NOD-like receptors, and influence the response of innate cells to invading pathogens. Endogenous danger signals can also influence local innate cells and orchestrate the inflammatory cascade. […] The activities of MMPs are controlled by several mechanisms including transcriptional regulation, proenzyme regulation, and specific tissue inhibitors of MMPs. The balance between MMPs and the various inhibitory mechanisms can regulate inflammation and determine the net amount of collagen deposited during the healing response.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  The precise function of MMP-2 and MMP-9 was elegantly demonstrated in a model of allergic airway inflammation and remodeling with MMP-2/, MMP-9/ and MMP-2/MMP-9/ double knockout mice. In these studies, the authors demonstrated that MMP-2, and more importantly MMP-9, were required for successful egression and clearance of inflammatory cells out of the inflamed tissue and into the airspaces. In the absence of these MMPs, cells were trapped within the parenchyma of the lung and were not able to move into the airspaces, which resulted in fatal asphyxiation. […] Once access to the site of tissue damage has been achieved, chemokine gradients recruit inflammatory cells. Neutrophils, eosinophils, lymphocytes, and macrophages are observed at sites of acute injury with cell debris and areas of necrosis cleared by phagocytes.

• #1 Role of interleukins in the pathogenesis of pulmonary fibrosis | Cell Death Discovery

  https://www.nature.com/articles/s41420-021-00437-9

  Therefore, the unbalanced secretion of cytokines may be the key cause of aberrant cell function that results in immunologic derangement in pulmonary fibrosis. […] Disorders of interleukins might affect the formation and development of pulmonary fibrosis. […] An increased IL-13 level and its inducible proteins and factors (such as periostin and CCL2) in IPF may accelerate the process of pulmonary fibrosis by inhibiting epithelial wound healing. […] Interleukins influence pulmonary fibrosis mainly through inflammation and immune response, but also via other ways. […] The above studies suggested that interleukins exacerbate or alleviate pulmonary fibrosis via a variety of ways. […] And some interleukins may serve a dual role in pulmonary fibrosis. […] The role of IL-4 in pulmonary fibrosis may be controversial and needs further investigation.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  TGF is derived from most cell lineages derived from the bone marrow including T cells, macrophages, eosinophils, and neutrophils and is one of the most widely studied pro-fibrotic cytokines. […] The potent activity of TGF is regulated at the post-transcriptional level by a latency-associated protein (LAP), which keeps TGF in an inactive state. […] The various and often opposing functions of TGF are likely explained by its various sources and cellular targets. […] In summary, inflammation and the recruitment of circulating granulocytes, lymphocytes, monocytes, macrophages, and fibrocytes, presents a continuous supply of pro- and anti-fibrotic players, vital for efficient wound repair but potentially deadly when not adequately controlled. […] An imbalance in chemokine production coupled with dysregulated cellular recruitment can result in an excess of pro-fibrotic IL-13 or TGF, a surplus of myofibroblasts, and can convert a normal wound-healing response into a pathological fibrotic reaction.

• #1 Pathogenesis of Idiopathic Pulmonary Fibrosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4116429/

  Levels of active transforming growth factor (TGF-) are increased in the lungs of patients with IPF. […] Whether v6-mediated TGF- activation contributes to IPF has yet to be proved, but possible profibrotic processes associated with TGF- activation include inhibition of AEC proliferation, differentiation of fibroblasts to myofibroblasts, and activation of programming that promotes mesenchymal transition of epithelial cells. […] Epithelial-to-mesenchymal transition (EMT) is the process by which epithelial cells acquire molecular and cell physiologic features commonly associated with mesenchymal cells following activation by specific growth factors, of which TGF- is the prototype. […] The evidence that alveolar cells exhibit EMT in IPF patients is based on immunohistochemical studies colocalizing epithelial cell and mesenchymal cell-associated proteins within IPF lungs.

• #1 Idiopathic pulmonary fibrosis: pathogenesis and management | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0730-2

  In this context of genetic susceptibility, the repeated micro-injury of the alveolar epithelium has been recognized as the first driver of an altered repair process where several lung cells develop aberrant behaviours, leading to the development and sustainment of the fibrotic process. […] The main pathogenetic actors in IPF are also illustrated in Fig. 1. […] The repetitive exposure of alveolar epithelium to microinjuries, as infections, cigarette smoke, environmental inhaled toxics, gastro-oesophageal reflux lead to damage of AEC1s. Dysfunctional AEC2s should regenerate damage cells, but their ability to re-establish normality is seriously impaired; this is the crucial moment of IPF pathogenesis. […] TGF-1 is probably the most important mediator involved in IPF pathogenesis. AEC2s may produce it as a consequence of actin/myosin-mediated cytoskeletal contraction induced by UPR, through 6 integrin activation.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  The cytokine profile from biopsy or BAL-derived cells or BAL fluid of IPF patients is rich in pro-inflammatory cytokines; IL-1, IL-8, IL-18, TNF, MCP-1 as well as Type-2 cytokines, and their receptors. […] Collectively, a cascade of failed regulatory mechanisms and hyper-secretion of cytokines, chemokines and growth factors culminates in an out-of-control fibroblast-mediated wound-healing response.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  The precise function of MMP-2 and MMP-9 was elegantly demonstrated in a model of allergic airway inflammation and remodeling with MMP-2/, MMP-9/ and MMP-2/MMP-9/ double knockout mice. In these studies, the authors demonstrated that MMP-2, and more importantly MMP-9, were required for successful egression and clearance of inflammatory cells out of the inflamed tissue and into the airspaces. In the absence of these MMPs, cells were trapped within the parenchyma of the lung and were not able to move into the airspaces, which resulted in fatal asphyxiation. […] The cytokine profile from biopsy or BAL-derived cells or BAL fluid of IPF patients is rich in pro-inflammatory cytokines; IL-1, IL-8, IL-18, TNF, MCP-1 as well as Type-2 cytokines, and their receptors. The mixed cytokine profile, derived primarily from inflammatory cells and leukocytes, can have significant effects on all aspects of wound healing including vascular remodeling, myofibroblast differentiation, EMT, TGF, and IL-13 production. In addition to the direct fibroblast-activating properties of TGF and IL-13, co-expression of these two cytokines in IPF has been observed.

• #1 Pathogenesis of fibrotic ILDs | PulmonaryFibrosis360.com

  https://www.pulmonaryfibrosis360.com/pulms/impact-of-pulmonary-fibrosis/pathophysiology-of-fibrotic-ilds

  Irrespective of the trigger for the lung injury, progressive fibrosing ILDs show commonalities not only in disease behavior but also in the pathogenic mechanisms that drive the fibrotic process. These pathogenic mechanisms culminate in irreversible loss of epithelial or endothelial barrier integrity, destruction of the lung architecture and loss of lung function. Excessive secretion of extracellular matrix can lead to a self-sustaining process of progressive fibrosis, where subsequent tissue stiffness and release of profibrotic cytokines further activates fibroblasts. Patients with chronic HP can develop a progressive fibrosing disease despite the absence of continued exposure to the inciting antigen. In exposure-related ILDs (e.g. silicosis), progression of symptoms and the severity of disease may occur even after termination of exposure to exogenous agents. A proportion of patients with ILD develop a progressive fibrosing phenotype independent from their ILD classification, with a disease course similar to IPF. Their pulmonary fibrosis is driven by an abnormal wound healing response following repeated injury, regardless of the cause of that injury. Mediators released in response to alveolar epithelial and/or vascular endothelial injury include chemokines, endothelin 1, thrombin and numerous growth factors. The abnormal healing response is believed to be due to an imbalance of such mediators, which creates a pro-fibrotic environment. The pro-fibrotic environment drives recruitment, proliferation, activation, and trans-differentiation of resident interstitial fibroblasts into contractile myofibroblasts. Myofibroblasts may also be derived from the trans-differentiation of other cell types, including pericytes, circulating fibrocytes, endothelial and epithelial cells. These myofibroblasts produce excessive extracellular matrix components. The accumulation of these components, combined with collagen cross-linking and contraction, distort the tissue architecture and alter gas exchange. This fibrotic scarring can also lead to occlusion of the local microvasculature, contributing to hypoxia. Once initiated, pulmonary fibrosis can become self-sustaining independent of the original trigger. This happens through multiple feed-forward amplification loops as a result of increased matrix stiffness, tissue pressure, and hypoxia. Pulmonary fibrosis is irreversible, and its progression leads to impaired gas exchange, increasing shortness of breath, a continually reduced quality of life, and ultimately to respiratory failure. Early recognition of pulmonary fibrosis is vital, given the significant morbidity and mortality associated with progressive fibrosing ILD.

• #1 Pathogenesis of Idiopathic Pulmonary Fibrosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4116429/

  In regions of normal or IPF lung, epithelial cells and fibroblasts are in close apposition. […] Another cytokine IPF AECs produce in increased amounts is PDGF, which can contribute to lung fibrosis by promoting fibroblast proliferation. […] A key issue to resolve to understand the pathobiology of IPF is why the disease has a relentlessly progressive clinical course. […] However, the surfactant mutations are the only genetic mutations with defined molecular pathways that can explain their contribution to lung fibrosis. […] The extracellular matrix is extensively modified in IPF lungs. […] Thus, it is possible that a change in the composition or stiffness of the extracellular matrix can contribute to the propagation of lung fibrosis. […] Regulation of gene expression by epigenetic influences has recently been recognized as an important mechanism by which environmental or other stresses can induce lasting changes in the phenotype of a cell, tissue, or organism. […] These findings suggest that DNA methylation and/or other epigenetic changes are important in the pathogenesis of IPF and that their enduring influences on gene expression could in part explain the relentless progression of the illness.

• #1 Idiopathic pulmonary fibrosis: pathogenesis and management | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0730-2

  The EMT is a molecular reprogramming of AEC2s, induced by UPR and enhanced by pro-fibrotic mediators and pathways. […] Other key pathways in IPF are a group of deregulated embryological programs, as the Wnt–catenin signalling, involved in EMT and fibrogenesis and activated by TGF-1, Sonic Hedgehog (Shh), gremlin-1, and phosphatase and tensin homologue (PTEN). […] The damage to alveolar structure and the loss of AECs, with disruption of basement membrane, involves alveolar vessels and leads to increased vascular permeability. […] The pathobiology of IPF is leaded by aberrant epithelial-mesenchymal crosstalk, but the inflammation may play an important role. […] The role of lymphocytes is still debated; certain lymphocytic cytokines are considered profibrotic, with direct effects on fibroblasts and myofibroblasts activity. […] In IPF lung levels of Interferon- (IFN-) are low.

• #1 Pathogenesis of Idiopathic Pulmonary Fibrosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4116429/

  The UPR, TGF-, and EMT are activated in patients with IPF, but how this activation occurs remains largely undefined. […] Overall, these results suggest that, in some circumstances, activation of the UPR may contribute to development of pulmonary fibrosis by enhancing TGF- secretion. […] The sections above outline genetic mutations predisposing to the development of lung fibrosis and how these mutations may lead to profibrotic molecular changes originating within epithelial cells. […] An alternative explanation for the lack of confirmation that genetic mutations lead directly to fibrosis is that exposure to additional environmental insults in genetically predisposed individuals is required for development of lung fibrosis. […] Epithelial cell dysfunction and aberrant epithelial-mesenchymal signaling lead to the activation of fibroblasts and the deposition and remodeling of matrix. […] The myofibroblast is the classic pathologic fibroblast phenotype described in IPF lungs.

• #1 Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis

  https://www.mdpi.com/2543-6031/91/1/5

  An important contributor to the development of idiopathic pulmonary fibrosis (IPF) is the alteration of the intracellular homeostasis of alveolar epithelial cells, which are mainly composed of alveolar type I epithelial cells (AT1), alveolar type II epithelial cells (AT2), as well as abnormal basaloid cells, resulting in aberrant epithelial repair, myofibroblast activation, and increased extracellular matrix deposition to form lung fibrosis. […] The activation of TGF-β in AT2 induces the production of fibrosis, which can be alleviated by inhibition of TGF-β transduction. […] The abnormal activation of fibroblasts in the pathological formation of idiopathic pulmonary fibrosis mainly involves the activation of TGF-β-related pathways JAK2-STAT3, pSmad2/3, and P38-MAPK. […] Mitochondrial dysfunction leads to increased reactive oxygen species, SASP formation, and cell senescence. […] The above work together to promote fibroblast proliferation and differentiation and induce fibrosis.

• #1 Pathogenesis of Idiopathic Pulmonary Fibrosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4116429/

  In the following review of the pathobiology of IPF we focus on data obtained from patients with the disease. […] The bleomycin model of lung injury is commonly used to study molecular pathways of pulmonary fibrosis. However, pathologic changes seen in this model do not recapitulate those seen in idiopathic pulmonary fibrosis. […] Early reports of cases of pulmonary fibrosis occurring in families suggested a genetic predisposition to some forms of the disease. […] Collectively, these studies show that mutations in the aging-related genes TERT and TERC are associated with up to 15% of FPF cases and rare sporadic IPF cases. […] The ER is the cellular compartment where secreted and membrane proteins are made, folded, and matured for packaging and trafficking via the Golgi complex. […] Studies have reported that markers of UPR activation are elevated in alveolar type II cells of patients with IPF.

• #1 Genetic Risk Factors for Idiopathic Pulmonary Fibrosis: Insights into | JIR

  https://www.dovepress.com/genetic-risk-factors-for-idiopathic-pulmonary-fibrosis-insights-into-i-peer-reviewed-fulltext-article-JIR

  The rs35705950 variant in the promoter region of the mucin 5B (MUC5B) gene was first identified in a 2011 genome-wide linkage study and is associated with an approximately 7-fold increased risk of developing IPF. […] The minor, disease-associated T allele at rs35705950 is a gain-of-function variant has been suggested to drive differential methylation of and transcription factor binding to the MUC5B leading to increased MUC5B expression. […] As the rs35705950 SNP leads to increases in MUC5B accumulation and presumably mucociliary stasis, this could result in chronic exposure of the distal airway to inhaled particles and pathogens. […] In addition to the clearance of particulate matter, MCC is essential for effectively removing pathogens from distal airspaces. […] Recent evidence has implicated the lung microbiome in IPF pathogenesis.

• #1 Mechanism Responsible for Development of Idiopathic Pulmonary Fibrosis Identified

  https://www.hcplive.com/view/mechanism-responsible-development-idiopathic-pulmonary-fibrosis-identified

  A contributing mechanism responsible for the development of idiopathic pulmonary fibrosis has been identified. […] The teams found that increased extracellular vesicles (EVs) function as carriers for signaling mediators, such as WNT-5A, in IPF and contribute to disease pathogenesis as a result. […] More specifically, TGF- in primary human lung fibroblasts induced WNT-5A, which was secreted on EVs in lung fibrosis, according to the authors. […] We were able to show in the study that increased levels of extracellular vesicles occur in IPF patients, which then act as carriers of WNT5A. […] Additionally, the teams also showed that reducing the number of vesicles decreased tissue scarring in Petri dish experiments.

• #1 Pulmonary fibrosis – Wikipedia

  https://en.wikipedia.org/wiki/Pulmonary_fibrosis

  Pulmonary fibrosis involves a gradual replacement of normal lung tissue with fibrotic tissue. Such scar tissue causes an irreversible decrease in oxygen diffusion capacity, and the resulting stiffness or decreased compliance makes pulmonary fibrosis a restrictive lung disease. Pulmonary fibrosis is perpetuated by aberrant wound healing, rather than chronic inflammation. It is the main cause of restrictive lung disease that is intrinsic to the lung parenchyma. […] Common genes implicated in fibrosis are Transforming Growth Factor-Beta (TGF-), Connective Tissue Growth Factor (CTGF), Epidermal Growth Factor Receptor (EGFR), Interleukin-13 (IL-13), Platelet-Derived Growth Factor (PDGF), Wnt/-catenin signaling pathway, and TNIK. […] TGF- is a cytokine that plays a critical role in the regulation of extracellular matrix (ECM) production and cellular differentiation. It is a potent stimulator of fibrosis, and increased TGF- signaling is associated with the development of fibrosis in various organs.

• #1 Pulmonary fibrosis – Wikipedia

  https://en.wikipedia.org/wiki/Pulmonary_fibrosis

  CTGF is a matricellular protein involved in ECM production and remodeling. It is up-regulated in response to TGF- and has been implicated in the development of pulmonary fibrosis. […] EGFR is a transmembrane receptor that plays a role in cellular proliferation, differentiation, and survival. Dysregulated EGFR signaling has been implicated in the development of pulmonary fibrosis, and drugs that target EGFR have been shown to have therapeutic potential in the treatment of the disease. […] IL-13 is a cytokine involved in regulating immune responses. It has been shown to promote fibrosis in the lungs by stimulating the production of ECM proteins and the recruitment of fibroblasts to sites of tissue injury. […] PDGF is a cytokine that plays a key role in the regulation of cell proliferation and migration. It is involved in the recruitment of fibroblasts to sites of tissue injury in the lungs, and increased PDGF signaling is associated with the development and progression of pulmonary fibrosis. […] Wnt/-catenin signaling plays a critical role in tissue repair and regeneration, and dysregulated Wnt/-catenin signaling has been implicated in the development of pulmonary fibrosis.

• #1 Molecular and cellular mechanisms of pulmonary fibrosis | Fibrogenesis & Tissue Repair | Full Text

  https://fibrogenesis.biomedcentral.com/articles/10.1186/1755-1536-5-11

  The role of macrophages in pulmonary fibrosis has been postulated for many years, and described mechanisms have included overexpression of reactive oxygen species, proteinase-activated receptors, Fas ligand, and profibrotic cytokines. […] Several animal models of pulmonary fibrosis have demonstrated that alveolar macrophages (AM) display a phenotype consistent with alternative activation. […] In patients with pulmonary fibrosis, the preponderance of data suggests that AM display an alternatively activated phenotype. […] The constellation of findings indicates that alternative activation of macrophages may play a mechanistic role in pulmonary fibrosis. […] The integrin v6, which is expressed principally in epithelial cells, is one of the v-integrins which has the ability to activate latent TGF- by binding to the tripeptide RGD sequence on TGF- latency-associated peptide (LAP).

• #1 Role of interleukins in the pathogenesis of pulmonary fibrosis | Cell Death Discovery

  https://www.nature.com/articles/s41420-021-00437-9

  Interleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. […] Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. […] We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. […] The immune response is also involved in the development of IPF. […] Th1/Th2 imbalance promotes pulmonary fibrosis through pro-fibrotic factors and inflammatory cytokines. […] A hypothesis called the phagocytosis-secretion-immunity network of macrophages explained the relationship between immune cells, cytokines, and pulmonary fibrosis.

• #1 Mechanism of lungs fibrosis in mycobacterial infection

  https://www.explorationpub.com/Journals/em/Article/1001187

  The participation of MMPs in the pathogenesis of TB is evidenced by the results of studies of other MMPs. There was a significant increase in the level of MMP-1 by 15 times, MMP-3 by 3.6 times, but a decrease in TIMP-1, TIMP-2 in sputum and bronchoalveolar lavage fluid in patients with pulmonary TB relative to control. […] An imbalance in the MMPs/TIMPs system leads to degradation of the connective tissue ECM and pathological remodeling, forming a morphological basis for violations of external respiration. […] The effectiveness of the composition consisting of dextrazide, an INH conjugate with OD enclosed in liposomesLEDZ, depended on the stage of granulomatosis it was administered. Such a difference in the effectiveness of LEDZ is explained by the selectivity of the effect of the composition on various links in the pathogenesis of pulmonary fibrosis.

• #1 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  Collectively, a cascade of failed regulatory mechanisms and hyper-secretion of cytokines, chemokines and growth factors culminates in an out-of-control fibroblast-mediated wound-healing response. Physiologically, IPF can dramatically compromise oxygen diffusion, lung function and is typically a fatal disease.

• #2 Role of interleukins in the pathogenesis of pulmonary fibrosis | Cell Death Discovery

  https://www.nature.com/articles/s41420-021-00437-9

  Interleukins, a group of cytokines participating in inflammation and immune response, are proved to be involved in the formation and development of pulmonary fibrosis. […] Despite the effects of interleukin-targeted treatment on experimental pulmonary fibrosis, clinical applications are lacking and unsatisfactory. […] We conclude that intervening in one type of interleukins with similar functions in IPF may not be enough to stop the development of fibrosis as it involves a complex network of regulation mechanisms. […] The immune response is also involved in the development of IPF. […] Th1/Th2 imbalance promotes pulmonary fibrosis through pro-fibrotic factors and inflammatory cytokines. […] A hypothesis called the phagocytosis-secretion-immunity network of macrophages explained the relationship between immune cells, cytokines, and pulmonary fibrosis.

• #2 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  A tightly regulated repair response following tissue injury is therefore critical. A well-coordinated influx of cells replace resident tissue cells, supply essential nutrients, and reform the tissue during a regenerative period. In some cases, this is followed by a period of fibroplasia, with too much extracellular matrix deposition and connective tissue formation. These events are often associated with vascular diseases and can give rise to many clinical conditions such as atherosclerosis, cirrhosis, scleroderma, asthma, and various types of pulmonary fibrosis. The regenerative process following tissue damage, despite having common mechanisms, can lead to various organ-specific disorders. This review will focus on pulmonary fibrotic conditions and, if known, present common regulatory mechanisms across diseases.

• #2 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  The precise function of MMP-2 and MMP-9 was elegantly demonstrated in a model of allergic airway inflammation and remodeling with MMP-2/, MMP-9/ and MMP-2/MMP-9/ double knockout mice. In these studies, the authors demonstrated that MMP-2, and more importantly MMP-9, were required for successful egression and clearance of inflammatory cells out of the inflamed tissue and into the airspaces. In the absence of these MMPs, cells were trapped within the parenchyma of the lung and were not able to move into the airspaces, which resulted in fatal asphyxiation. […] The cytokine profile from biopsy or BAL-derived cells or BAL fluid of IPF patients is rich in pro-inflammatory cytokines; IL-1, IL-8, IL-18, TNF, MCP-1 as well as Type-2 cytokines, and their receptors. The mixed cytokine profile, derived primarily from inflammatory cells and leukocytes, can have significant effects on all aspects of wound healing including vascular remodeling, myofibroblast differentiation, EMT, TGF, and IL-13 production. In addition to the direct fibroblast-activating properties of TGF and IL-13, co-expression of these two cytokines in IPF has been observed.

• #2 Pulmonary fibrosis: pathogenesis, etiology and regulation | Mucosal Immunology

  https://www.nature.com/articles/mi200885

  Collectively, a cascade of failed regulatory mechanisms and hyper-secretion of cytokines, chemokines and growth factors culminates in an out-of-control fibroblast-mediated wound-healing response. Physiologically, IPF can dramatically compromise oxygen diffusion, lung function and is typically a fatal disease.

• #2 Idiopathic pulmonary fibrosis: pathogenesis and management | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0730-2

  Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive disease characterized by the aberrant accumulation of fibrotic tissue in the lungs parenchyma, associated with significant morbidity and poor prognosis. […] Over the last two decades much has been clarified about the pathogenic pathways underlying the development and progression of the lung scarring in IPF. […] Despite the comprehensive understanding of IPF pathogenesis remains elusive, research efforts in the last few years have reached important milestones. Several environmental and microbial exposures have been proposed as playing roles in IPF pathobiology that might be far from collateral, making the concept of idiopathic less compelling. Individual genetic and epigenetic factors remain the most important for the development of the fibrotic process, although the contribution of the variants so far identified, or their interaction with the putative external factors has yet to be clarified.

• #2 Idiopathic pulmonary fibrosis: pathogenesis and management | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0730-2

  In this context of genetic susceptibility, the repeated micro-injury of the alveolar epithelium has been recognized as the first driver of an altered repair process where several lung cells develop aberrant behaviours, leading to the development and sustainment of the fibrotic process. […] The main pathogenetic actors in IPF are also illustrated in Fig. 1. […] The repetitive exposure of alveolar epithelium to microinjuries, as infections, cigarette smoke, environmental inhaled toxics, gastro-oesophageal reflux lead to damage of AEC1s. Dysfunctional AEC2s should regenerate damage cells, but their ability to re-establish normality is seriously impaired; this is the crucial moment of IPF pathogenesis. […] TGF-1 is probably the most important mediator involved in IPF pathogenesis. AEC2s may produce it as a consequence of actin/myosin-mediated cytoskeletal contraction induced by UPR, through 6 integrin activation.

• #2 Idiopathic pulmonary fibrosis: pathogenesis and management | Respiratory Research | Full Text

  https://respiratory-research.biomedcentral.com/articles/10.1186/s12931-018-0730-2

  The EMT is a molecular reprogramming of AEC2s, induced by UPR and enhanced by pro-fibrotic mediators and pathways. […] Other key pathways in IPF are a group of deregulated embryological programs, as the Wnt–catenin signalling, involved in EMT and fibrogenesis and activated by TGF-1, Sonic Hedgehog (Shh), gremlin-1, and phosphatase and tensin homologue (PTEN). […] The damage to alveolar structure and the loss of AECs, with disruption of basement membrane, involves alveolar vessels and leads to increased vascular permeability. […] The pathobiology of IPF is leaded by aberrant epithelial-mesenchymal crosstalk, but the inflammation may play an important role. […] The role of lymphocytes is still debated; certain lymphocytic cytokines are considered profibrotic, with direct effects on fibroblasts and myofibroblasts activity. […] In IPF lung levels of Interferon- (IFN-) are low.

• #2 Cellular and Molecular Mechanisms in Idiopathic Pulmonary Fibrosis

  https://www.mdpi.com/2543-6031/91/1/5

  An important contributor to the development of idiopathic pulmonary fibrosis (IPF) is the alteration of the intracellular homeostasis of alveolar epithelial cells, which are mainly composed of alveolar type I epithelial cells (AT1), alveolar type II epithelial cells (AT2), as well as abnormal basaloid cells, resulting in aberrant epithelial repair, myofibroblast activation, and increased extracellular matrix deposition to form lung fibrosis. […] The activation of TGF-β in AT2 induces the production of fibrosis, which can be alleviated by inhibition of TGF-β transduction. […] The abnormal activation of fibroblasts in the pathological formation of idiopathic pulmonary fibrosis mainly involves the activation of TGF-β-related pathways JAK2-STAT3, pSmad2/3, and P38-MAPK. […] Mitochondrial dysfunction leads to increased reactive oxygen species, SASP formation, and cell senescence. […] The above work together to promote fibroblast proliferation and differentiation and induce fibrosis.

• #2 Pathogenesis of Idiopathic Pulmonary Fibrosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC4116429/

  In regions of normal or IPF lung, epithelial cells and fibroblasts are in close apposition. […] Another cytokine IPF AECs produce in increased amounts is PDGF, which can contribute to lung fibrosis by promoting fibroblast proliferation. […] A key issue to resolve to understand the pathobiology of IPF is why the disease has a relentlessly progressive clinical course. […] However, the surfactant mutations are the only genetic mutations with defined molecular pathways that can explain their contribution to lung fibrosis. […] The extracellular matrix is extensively modified in IPF lungs. […] Thus, it is possible that a change in the composition or stiffness of the extracellular matrix can contribute to the propagation of lung fibrosis. […] Regulation of gene expression by epigenetic influences has recently been recognized as an important mechanism by which environmental or other stresses can induce lasting changes in the phenotype of a cell, tissue, or organism. […] These findings suggest that DNA methylation and/or other epigenetic changes are important in the pathogenesis of IPF and that their enduring influences on gene expression could in part explain the relentless progression of the illness.

• #2 Pulmonary fibrosis: pathogenesis, etiology and regulation

  https://pmc.ncbi.nlm.nih.gov/articles/PMC2675823/

  The cytokine profile from biopsy or BAL-derived cells or BAL fluid of IPF patients is rich in pro-inflammatory cytokines; IL-1, IL-8, IL-18, TNF, MCP-1 as well as Type-2 cytokines, and their receptors. […] Collectively, a cascade of failed regulatory mechanisms and hyper-secretion of cytokines, chemokines and growth factors culminates in an out-of-control fibroblast-mediated wound-healing response.

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