Materiały źródłowe

• #1 Interstitial Lung Disease – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK541084/

  Interstitial lung disease (ILD), sometimes called diffused parenchymal diseases, describes a heterogeneous collection of distinctive lung disorders classified on the grounds of shared clinical, radiographic, physiologic or pathologic factors. […] The pathogenetic sequence in actuality involves a series of inflammation and fibrosis that extends beyond disrupting the interstitial bed (as the name implies) to changing the parenchyma (alveoli, alveolar ducts, and bronchioles). […] Many of the subsets of the disease are of unknown etiology. Regardless, they all ultimately share the same manner of development. The morphological changes seen histologically result from a sequence of inflammation within the parenchyma, which is the portion of the lung involved in gas exchange (the alveoli, the alveolar ducts, and the bronchioles). This compartment is the habitat to various proteins and pro-fibrotic elements. These proteins, after repeated cycles of activation, give rise to accumulation of connective tissue. […] The trigger can be a known agent that deposited within the lung tissues. In some cases, the fibrosis arises spontaneously.

• #1 Interstitial lung disease – Symptoms and causes – Mayo Clinic

  https://www.mayoclinic.org/diseases-conditions/interstitial-lung-disease/symptoms-causes/syc-20353108

  Interstitial lung disease seems to occur when an injury to your lungs causes a healing response that isn’t proper. […] But in ILD, the repair process doesn’t work properly. Tissue in and around the lungs’ air sacs, called alveoli, becomes inflamed, scarred and thickened. This makes it harder for oxygen to pass into your bloodstream. […] Certain diseases or conditions may lead to interstitial lung disease. […] These diseases result in an immune response that isn’t proper and may cause tissue inflammation and scarring in the body, including in the lungs. […] The list of substances and conditions that can lead to interstitial lung disease is long. Even so, in some people, the cause is never found. Conditions without a known cause are grouped together under the label of idiopathic interstitial pneumonias. […] IPF is a typically progressive lung disease that occurs when lung tissue becomes damaged and scarred what’s known as fibrosis. […] This thickened, stiff tissue makes it harder for your lungs to work properly. The most common type of ILD, IPF often gets worse and can’t be reversed.

• #1 Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease | Inflammation and Regeneration | Full Text

  https://inflammregen.biomedcentral.com/articles/10.1186/s41232-024-00345-2

  Although fibrosis is a normal physiological response that occurs as part of wound healing and host defense against pathogens, this process can malfunction, causing exaggerated pro-inflammatory and profibrotic responses. This leads to fibroblast activation and differentiation into myofibroblasts, extracellular matrix (ECM) deposition, and remodeling of the functional lung tissue, resulting in tissue stiffness and compromised gaseous exchange. […] The initial triggers of fibrotic ILD can be broadly categorized into two types: epithelial cell injury, as is the case of IIPs such as IPF, and immune activation, which can result from autoimmune disease or exposure to a persistent antigen. […] Epithelial cell injury is an important initial step in the progression of lung fibrosis, particularly in IPF, and has multiple potential triggers, including environmental exposure from smoking, occupational hazards, air pollution, and viruses.

• #1 Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease | Inflammation and Regeneration | Full Text

  https://inflammregen.biomedcentral.com/articles/10.1186/s41232-024-00345-2

  Interstitial lung diseases (ILDs) are a diverse group of conditions characterized by inflammation and fibrosis in the lung. In some patients with ILD, a progressive fibrotic phenotype develops, which is associated with an irreversible decline in lung function and a poor prognosis. […] The pathological mechanisms that underlie this process culminate in fibroblast activation, proliferation, and differentiation into myofibroblasts, which deposit extracellular matrix proteins and result in fibrosis. Upstream of fibroblast activation, epithelial cell injury and immune activation are known initiators of fibrosis progression, with multiple diverse cell types involved. […] Knowledge of the pathological mechanisms that drive progressive fibrosis in patients with ILD has expanded, with the role of alveolar endothelial cells, the immune system, and fibroblasts better elucidated. Drugs that target novel mechanisms hold promise for expanding the future therapeutic armamentarium for progressive fibrotic ILD.

• #1 Pathogenesis of fibrotic ILDs | PulmonaryFibrosis360.com

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

  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. […] 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.

• #1 Pathogenesis of Interstitial Lung Disease in Children and Adults

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3207223/

  The lung alveolar epithelium is the final barrier interface between the bloodstream and the environment. […] Intrinsic or extrinsic epithelial cell stress can lead to surfactant dysfunction, epithelial apoptosis, impaired innate immunity, altered injury response, and promote abnormal epithelial-mesenchymal signaling, and a variable degree of remodeling up to and including fibrosis. […] Genetic disorders in surfactant production and function in the lung have been demonstrated to cause significant, often severe primary lung disease in full-term infants, a variable spectrum of alveolar and interstitial alterations in older children, and fibrotic disease in adults. […] The relationship of these disorders to pathophysiology of ILD and presentation across the lifespan will be discussed here.

• #1 Diagnosis and management of interstitial lung disease | Translational Respiratory Medicine | Full Text

  https://transrespmed.springeropen.com/articles/10.1186/2213-0802-2-4

  There is increasing awareness that an abnormal degree of gastroesophageal reflux (GER) combined with aspiration may play a significant role in the pathogenesis of a number of forms of ILD. […] It has been suggested that reflux of foregut contents into the proximal esophagus via a dysfunctional lower esophageal sphincter (e.g. presence of a hiatal hernia) can predispose to (micro)aspiration, which may initiate and/or drive lung inflammation that can progress to pulmonary fibrosis in a susceptible individual, and accumulating evidence has linked GER with aspiration to IPF pathogenesis. […] Our understanding of the natural history and pathobiology of various forms of ILD continues to evolve, and classification systems, such as that for the IIPs, must be periodically revised to incorporate new knowledge.

• #1 Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease | Inflammation and Regeneration | Full Text

  https://inflammregen.biomedcentral.com/articles/10.1186/s41232-024-00345-2

  Overall, the changes in epithelial cellular composition lead to abnormal secretion of profibrotic mediators. These include transforming growth factor (TGF)-1, platelet-derived growth factor (PDGF), fibroblast growth factors (FGFs), connective tissue growth factor, tumor necrosis factor (TNF), endothelin-1, CXC chemokine ligand 12, and osteopontin. The secretion of these factors from alveolar epithelial cells drives the process of fibroblast migration, proliferation, activation, and differentiation into myofibroblasts that results in lung fibrosis. […] A multitude of genetic and cellular changes contribute to progressive fibrosis in ILD. Genomic studies have unveiled some genetic mechanisms that may be involved. […] Cellular senescence, a state of non-reversible cell cycle arrest that can be induced by telomere attrition, has been identified as a significant contributor to the pathophysiology of UIP, irrespective of underlying etiology.

• #1 Pathogenesis of Interstitial Lung Disease in Children and Adults

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3207223/

  Many types of ILDs follow some type of injury to the distal airspaces (eg, infection, radiation, environmental exposures), resulting in damage to the epithelial or endothelial layers and the associated basement membrane. […] Inflammation is present in many types of ILD, and many forms of ILD are triggered by inflammatory events, such as infection or hypersensitivity. […] However, lung inflammation does not necessarily result in fibrotic remodeling, and fibrosis can occur in the absence of inflammation; therefore, inflammation has a prominent, but not an essential, role in lung remodeling and fibrosis. […] Selman et al. had a major impact on the field by proposing reconsideration of IPF as a disorder of epithelial-fibroblast interaction. […] Thus it seems that many of the cellular and molecular events critical to modeling of the lung are recapitulated during the remodeling following injury or during the pathogenesis of ILD.

• #1 Pathogenic pathways to fibrogenesis | PulmonaryFibrosis360.com

  https://www.pulmonaryfibrosis360.com/rheums/ra-ild/common-pathophysiology-of-fibrotic-ctd-ilds

  Based on the pathogenesis of fibrotic interstitial lung disease in connective tissue diseases, a new treatment paradigm of CTD-ILDs suggests to not only target inflammation but also fibrosis. […] A complex interplay of inflammatory, fibrotic and vascular processes leads to the activation and proliferation of fibroblasts, their differentiation into myofibroblasts, and the excessive secretion of extracellular matrix. […] Irrespective of the clinical diagnosis, there are commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis. […] Once pulmonary fibrosis has become self-sustaining, fibroblasts can become partially independent of external stimulation and the initiating inflammatory response. […] Progressive fibrosing CTD-ILDs are driven by a common pathophysiology.

• #1 Disease pathogenesis in interstitial lung disease | Thorax

  https://thorax.bmj.com/content/64/Suppl_4/A37

  The pathogenesis of idiopathic pulmonary fibrosis remains a controversial subject. The prevailing hypothesis favours an aberrant wound healing response where epithelial injury stimulates myofibroblast differentiation with collagen deposition and resultant fibrosis. […] We hypothesised that the profibrotic alternatively activated macrophage is critical to lung fibrosis progression. […] We have shown for the first time the critical role that monocytes and macrophages play in the pathogenesis of pulmonary fibrosis. Our data suggest that it is the profibrotic alternatively activated macrophage that is the key player involved in this process. […] Pulmonary fibrosis is the end stage of various conditions, lacks satisfactory treatment options and results in significant morbidity and mortality. Alveolar epithelial cell (AEC) injury plays a central role in the pathogenesis of pulmonary fibrosis; restoration of epithelial integrity is required for re-establishment of normal alveolar architecture.

• #1 Systemic sclerosis and interstitial lung disease: From pathogenesis, to screening, diagnosis, and classification | Revista Colombiana de Reumatología

  https://www.elsevier.es/es-revista-revista-colombiana-reumatologia-374-articulo-systemic-sclerosis-interstitial-lung-disease-S0121812323000695

  Repetitive and sustained injury of alveolar endothelial and epithelial cells is believed to be the initial step for the development of ILD-SSc. […] The pathologic assessment of lung tissue from patients with SSc-ILD has revealed a marked increase in expression of ET-1 and its receptors. […] The immunohistopathological investigation of lung tissue has demonstrated the occurrence of EndoMT in SSc-ILD. […] Alveolitis, the infiltration of alveoli with inflammatory and immune cells, is reflected in an increased percentage of neutrophils, lymphocytes or eosinophils in BAL. […] The results of numerous studies revealed a prominent granulocytosis (neutrophilia and eosinophilia) in BAL from patients with SSc-ILD. […] Activated specific adaptive immune cells including T helper (Th)2 cells, Th22 cells, Th17 cells, and B cells participate in the pathogenesis of SSc-ILD.

• #1

  https://journals.lww.com/ijru/fulltext/2021/16001/genetics_and_pathogenesis_of_connective_tissue.5.aspx

  Fibrocytes are circulating myeloid-derived cells that migrate to tissues and can differentiate into myofibroblasts. Myofibroblasts are the main effector cells of fibrosis. They synthesize extracellular matrix components and contain microfilaments in their cytoplasm similar to those of smooth muscle cells conferring contractile function to them. These functions lead to structural remodeling and are thus the key mediators of the loss of alveolar function. The persistence and self-perpetuation of this process lead to pathology. An important requirement for the persistence of this process is the myofibroblasts in CTD-ILD seem to be resistant to apoptosis. […] Several cytokines and chemokines have been studied and shown to play a role in the pathogenesis of pulmonary fibrosis. TGF b-1 is the prototypical, most well studied, and most potent fibrogenic mediator in pulmonary fibrosis. Platelet-derived growth factor is another important mediator of fibrosis. Interleukins such as IL-1, IL-17, IL-6, and IL-13 are important mediators of inflammation and fibrosis.

• #1 Pathogenesis of interstitial lung disease in systemic sclerosis

  https://www.degruyter.com/document/doi/10.2478/rir-2024-0020/html?lang=en

  Interstitial lung disease (ILD) is a frequent important complication of systemic sclerosis (SSc). Factors relevant to aetiopathogenesis of SSc are also central to SSc-ILD. Severity of SSc-ILD is variable but it has a major impact on morbidity and mortality. Factors determining SSc-ILD susceptibility reflect the genetic architecture of SSc and are increasingly being defined. […] Examination of blood and tissue samples and observational clinical research together with integrated analysis of in vitro and in vivo preclinical models have elucidated pathogenic mechanisms of SSc-ILD. These have confirmed the potential importance of immune mechanisms in the innate and adaptive immune systemic as well as a significant role for profibrotic pathways especially transforming growth factor beta (TGFbeta) and its regulators and downstream mediators.

• #1 Systemic sclerosis and interstitial lung disease: From pathogenesis, to screening, diagnosis, and classification | Revista Colombiana de Reumatología

  https://www.elsevier.es/es-revista-revista-colombiana-reumatologia-374-articulo-systemic-sclerosis-interstitial-lung-disease-S0121812323000695

  The dysregulation of B cell immunity including hyperactivation of B cells with production of autoantibodies, alteration of B cell homeostasis, and imbalance between B cell subsets, plays a fundamental role in the pathogenesis of SSc. […] Myofibroblasts and fibroblasts are the main driving cells leading to fibrosis through excessive ECM deposition in ILD.

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

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

  AEC2s may produce it as a consequence of actin/myosin-mediated cytoskeletal contraction induced by UPR, through 6 integrin activation. […] 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 contribution of mesenchymal cells, and particularly of fibroblasts and myofibroblasts is crucial for IPF pathogenesis; these cells are recruited, activated and induced to differentiate, trans-differentiate and proliferate by the abnormal biochemical environment created by activated epithelial and endothelial cells.

• #1 Understanding Interstitial Lung Diseases Associated with Connective Tissue Disease (CTD-ILD): Genetics, Cellular Pathophysiology, and Biologic Drivers

  https://www.mdpi.com/1422-0067/24/3/2405

  Dysregulation of lung repair following any type of stimulation is the basic pathogenesis of ILD and lung fibrosis. Lung repair and regeneration are regulated by multiple major pathways, including developmental pathways such as TGF-β, Wnt, Sonic hedgehog (SHH), inflammatory pathways, cellular senescence, amongst others. Abnormal activation of these pathways contributes to lung fibrosis. […] TGF-β regulatory signaling, specifically the TGF-β1 isoform, is the central developmental pathway in lung fibrosis pathogenesis. Specifically, TGF-β seems to be a common final pathway of many profibrotic signals. Current FDA-approved anti-fibrotic agents, Pirfenidone and Nintedanib, and a combination of both are being studied in CTD-ILD as targeting agents of the TGF-β downstream signaling molecules further implicating this signaling pathway in CTD-ILD and fibrosis.

• #1 Pathogenesis of fibrotic ILDs | PulmonaryFibrosis360.com

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

  While ILDs differ, common pathogenic pathways to fibrogenesis are shared. […] 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. […] 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.

• #1 Disease pathogenesis in interstitial lung disease | Thorax

  https://thorax.bmj.com/content/64/Suppl_4/A37

  Transforming growth factor (TGF) is a pleiotropic cytokine with a central role in the pathogenesis of IPF. […] LPA increases Itgb6 and Lpar2 expression via an autocrine loop of TGF activation. […] We have demonstrated that EA is unlikely to compromise cellular energy state, but significantly reduces cellular redox status. Furthermore, our findings suggest that the presence of EA may enhance H2O2-induced cell injury via potentiation of protein carbonylation and by metabolic derangements.

• #1 Interstitial Lung Diseases and Non-Small Cell Lung Cancer: Particularities in Pathogenesis and Expression of Driver Mutations

  https://www.mdpi.com/2073-4425/15/7/934

  Interstitial lung diseases (ILD) constitute a heterogenous group of chronic lung diseases, characterized by inflammation and fibrosis. The pathogenesis of IPF is a complex process that includes responses to epithelial damage and several molecular mechanisms that lead to fibrosis. The recurrent alveolar epithelial cell (AEC) injury model is the main pathogenetic mechanism that is described. Predisposing factors, such as genetic, environmental, epigenetic, and immunologic, cause epithelial damage and dysregulated epithelial repair. This results in abnormal fibroblast proliferation, dilatation of the extracellular matrix, and loss of normal lung architecture. The molecular events that lead to IPF orchestrate all cell types that participate in epithelial injury repair and lung fibrosis (alveolar epithelial cells, fibroblasts, endothelial cells, and immune cells). Data from scRNA-seq comparing IPF and control lung tissue have provided evidence for the presence of an aberrant epithelial cell type, which expresses markers including matrix metalloproteinase 7 (MMP7), integrin αVβ6, cellular senescence, and epithelial–mesenchymal transition (EMT) and represents a major driver of IPF pathogenesis. IL-1β is important in the normal differentiation of AT2 cells into AT1 cells. IL-1β signaling is another mechanism by which chronic inflammation leads to fibrosis. The Wnt signaling pathway and its nuclear mediator β-catenin are involved in the development of normal lung tissue and organogenesis. It plays a crucial role in the differentiation of the normal bronchial and alveolar epithelial cells. The Wnt pathway is implicated in the pathogenesis of pulmonary fibrosis. After injury, fibroblasts maintain AT2 cells through Wnt signaling. Sustained Wnt signaling through β-catenin inhibits AT2 cell differentiation and leads to lung fibrosis. AT2 cells prevail in the expression of IL-1β and cause fibrosis through TGF-β. It is also described the role of β-catenin signaling in the epithelial–mesenchymal transition (EMT), which is important in embryonic development, tumor progression, and fibrosis. Epithelial–mesenchymal transition (EMT) is a step in normal injury repair and is characterized by the loss of cell-to-cell adhesion molecules, such as E-cadherin and is regulated in IPF and cancer. EMT is probably a process where epithelial cells differentiate into mesenchymal cells and promote local fibrosis. Transforming growth factor-β (TGF-β) is the factor that has a role in fibrosis. In normal healing after injury, fibroblasts, differentiation of myofibroblasts, and deposition of extracellular matrix take place in order to close the trauma. Upregulation of the TGF-β signaling pathway is observed in fibrotic diseases, which promotes activation of fibrotic mesenchymal cells and deposition of extracellular matrix. TGF-β signaling has been involved in pulmonary fibrosis. TGF-β1 activates HMGB1, RELM-β, Slit2, and Fstl1 by cooperating with Smad2 and Smad3 and influences the three steps of idiopathic pulmonary fibrosis (EMT, myofibroblast differentiation, and fibrogenesis). Familiar pulmonary fibroses represent about 5–20% of cases with IPF. This fact suggests that molecular events are implicated in the pathogenesis of the disease. The most common mutation is the MUC5B risk allele. The MUC5B promoter polymorphism is related to mucociliary clearance epithelial activity and is associated with interstitial lung disease. Overexpression of MUC5B leads to mucus hypersecretion in bronchoalveolar epithelium and promotes inflammation and injury. Toll-interacting protein is an intracellular adaptor protein that has a role in inflammation, immune response, and lung epithelial cell apoptosis. Polymorphism in the promoter for the Toll-interacting protein (TOLLIP) is another genetic event that is associated with an increased risk of developing IPF. These genetic variants provide novel advantages for targeted therapies in IPF. Telomeres are nucleotide sequences that stabilize chromosome edges in order to prevent chromosome shortening during cell replication. Telomerase-related mutations (TRM) are observed in familiar and sporadic IPF. Several mutations of this protein complex have been described, with TERC and TERT being the most common. Patients with ILD have an increased risk of developing lung cancer. In a metanalysis of 35 studies, 13.5% of patients with IPF developed non-small cell lung cancer (NSCLC). There are several common molecular events that are observed in lung cancer and in patients with ILD. Mutations in the TP53 gene have been found in patients with squamous cell carcinoma of the lung and IPF. Decreased PTEN expression and hyperactivation of Akt have been discovered in the alveolar epithelial cells and fibroblastic areas of human IPF lungs and patients with lung cancer. That makes PTEN/P13K/Akt signaling a crucial pathogenetic mechanism and a potential therapeutic target for IPF and NSCLC. Cancer-associated fibroblasts (CAFs) are specific cell types that determine tumors biological behavior. These results suggest the need for more research to discover the mechanisms linking pulmonary fibrosis and lung carcinogenesis. The treatment of patients with IPF and lung cancer is challenging because surgery, radiation therapy, or chemotherapy may cause exacerbations of the underlying ILD, which can lead to complications and death. Thus, it is important to find targeted therapies with fewer complications for these patients in order to decrease morbidity and mortality.

• #1 Understanding the mechanisms of drug-associated interstitial lung disease | British Journal of Cancer

  https://www.nature.com/articles/6602065

  Although the mechanisms by which lung fibrosis develops are not fully understood, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. […] Increased production of transforming growth factor beta (TGF-β) was demonstrated in epithelial cells of terminal airways and alveoli in idiopathic pulmonary fibrosis. […] In addition to multiple effects on the process of fibrogenesis, TGF-β1 can induce apoptosis in various cells. […] The mechanism of TGF-β1-mediated apoptosis probably varies among cell types. […] TGF-β1 is a potent inducer of apoptosis through caspase-3 activation and the downregulation of p21. […] It is also an enhancer of Fas-mediated apoptosis of lung epithelial cells.

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

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

  Despite the comprehensive understanding of IPF pathogenesis remains elusive, research efforts in the last few years have reached important milestones. […] The main pathogenetic actors in IPF are also illustrated in Fig. 1. […] 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 repetitive exposure of alveolar epithelium to microinjuries, as infections, cigarette smoke, environmental inhaled toxics, gastro-oesophageal reflux lead to damage of AEC1s. […] The cellular activity leads to protein over-expression and endoplasmic reticulum stress (ERS), a protective pathway that occurs when there is an imbalance between cellular demand for protein synthesis and the endoplasmic reticulum capacity to work properly.

• #1 Pathogenesis of Interstitial Lung Disease in Children and Adults

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3207223/

  An important insight that has emerged from the study of surfactant dysfunction disorders is that mutations in a single gene can cause different disease manifestations at different ages and stages of development. […] Thus it is critical to consider age and developmental stage, or auxotype, in addition to genotype, in considering the phenotype of a diffuse lung disease.

• #1 Pathogenesis of Interstitial Lung Disease in Children and Adults

  https://pmc.ncbi.nlm.nih.gov/articles/PMC3207223/

  Interstitial lung diseases (ILDs) occur across the lifespan, from birth to advanced age. […] The historical approach of classifying childhood ILD (chILD) using adult classification schemes may therefore have done more harm than good. […] Thus comparison of the pathophysiology of ILD in children and adults in the context of lung development is useful in understanding the pathogenesis of these disorders, and may lead to novel therapeutic interventions for ILDs at all ages. […] Most ILDs share in common structural remodeling of the distal airspaces leading to impaired gas exchange. […] However, the more recent paradigm has been tissue injury with aberrant wound healing, often resulting in collagenous fibrosis. […] Fibrosis per se is more prominent in adult ILDs than in chILD disorders.

• #1 Interstitial lung disease – Wikipedia

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

  Idiopathic pulmonary fibrosis is interstitial lung disease for which no obvious cause can be identified (idiopathic) and is associated with typical findings both radiographic (basal and pleural-based fibrosis with honeycombing) and pathologic (temporally and spatially heterogeneous fibrosis, histopathologic honeycombing, and fibroblastic foci). […] ILD may be classified as to whether its cause is not known (idiopathic) or known (secondary). […] Idiopathic interstitial pneumonia is the term given to ILDs with an unknown cause. They represent the majority of cases of interstitial lung diseases (up to two-thirds of cases). […] Connective tissue related disease represents approximately 25% of all cases of ILD. […] Smoking-related interstitial fibrosis (SRIF) is an example of a type of interstitial lung disease known to be caused by smoking.

• #1 Pathogenesis of idiopathic pulmonary fibrosis – UpToDate

  https://www.uptodate.com/contents/pathogenesis-of-idiopathic-pulmonary-fibrosis

  Pathogenesis of idiopathic pulmonary fibrosis […] An overview of the pathogenesis of IPF, including the central role of fibroblast proliferation and abnormal collagen metabolism will be presented here. […] The characteristic histopathologic features of usual interstitial pneumonia (UIP) in patients with idiopathic pulmonary fibrosis (IPF) include abnormal proliferation of mesenchymal cells, varying degrees of fibrosis, overproduction and disorganized deposition of collagen and extracellular matrix, and distortion of pulmonary architecture and subpleural cystic airspaces (3 to 10 mm diameter) called honeycomb cysts. […] Fibroblast foci are clusters of fibroblasts and myofibroblasts that lie in continuity with the established fibrosis and are a characteristic histologic feature of UIP. […] The end result of the fibrotic process is a complex reticulum that is highly interconnected and extends from pleura into the underlying parenchyma.

• #1 Pathogenic pathways to fibrogenesis | PulmonaryFibrosis360.com

  https://www.pulmonaryfibrosis360.com/rheums/ra-ild/common-pathophysiology-of-fibrotic-ctd-ilds

  While CTDs differ, common pathogenic pathways to fibrogenesis are shared irrespective of the trigger for the lung injury. […] The pathogenesis of fibrotic interstitial lung disease in connective tissue diseases involves a complex interplay of inflammatory and fibrotic processes. […] Fibrotic ILD often develops early in the course of a CTD. […] At the cellular level, ILD in CTDs is triggered by repeated tissue injury which induces an inflammatory response, and releases probiotic mediators, including VEGF, PDGF and FGF. […] Activation of leukocytes also produces profibrotic mediators leading to further activation of the fibrotic process with excessive secretion of extracellular matrix. […] Excess extracellular matrix increases lung tissue stiffness, further activating fibroblasts in a feed-forward loop of self-sustaining progressive pulmonary fibrosis.

• #1 Systemic sclerosis and interstitial lung disease: From pathogenesis, to screening, diagnosis, and classification | Revista Colombiana de Reumatología (English Edition)

  https://www.elsevier.es/es-revista-revista-colombiana-reumatologia-english-edition–474-articulo-systemic-sclerosis-interstitial-lung-disease-S2444440524000396

  Repetitive and sustained injury of alveolar endothelial and epithelial cells is believed to be the initial step for the development of ILD-SSc. […] Thrombin, a procoagulant factor, is released after tissue and vascular injury. […] Another possible mediator released after lung injury is endothelin-1 (ET-1) which is a strong vasoconstrictor and is secreted by endothelial cells, epithelial cells, and alveolar macrophages. […] The pathologic assessment of lung tissue from patients with SSc-ILD has revealed a marked increase in expression of ET-1 and its receptors. […] Alveolar epithelial cells (AECs) divide into two cell subsets. […] The level of KL-6 increases with alveolar epithelial damage or cellular regeneration. […] The immunohistopathological investigation of lung tissue has demonstrated the occurrence of EndoMT in SSc-ILD.

• #1 Understanding Interstitial Lung Diseases Associated with Connective Tissue Disease (CTD-ILD): Genetics, Cellular Pathophysiology, and Biologic Drivers

  https://www.mdpi.com/1422-0067/24/3/2405

  In CTD-ILD, dysregulation of regulator pathways in inflammation is a primary culprit. However, confirmatory studies are required. Understanding these pathogenetic mechanisms is necessary for developing and tailoring more targeted therapy and provides newly discovered disease biomarkers for early diagnosis, clinical monitoring, and disease prognostication. This review highlights the central CTD-ILD pathogenesis and biological drivers that facilitate the discovery of disease biomarkers. […] The underlying pathogenesis of CTD-ILD and CTD-ILD/fibrosis is generally controversial and not well-characterized as in IPF. Given some overlap mechanisms, one can extrapolate IPF pathogenesis to CTD-ILD and fibrosis. Nonetheless, it is widely believed that dysregulation of inflammatory pathways is the primary cellular mechanism that drives profibrotic cascades causing aberrant tissue remodeling and fibroproliferation.

• #1 Understanding the mechanisms of drug-associated interstitial lung disease | British Journal of Cancer

  https://www.nature.com/articles/6602065

  Drugs have been implicated in lung injury as a result of direct pharmacological action, persistence or metabolism in the tissue, or via the production of a reactive metabolite or metabolites. […] The result of this apparent drug-associated injury ranges from cellular dysfunction through to cell death (apoptosis) and alteration of repair mechanisms that are essential in replacing critical tissue elements and function. […] There is limited knowledge on how timing of drug administration or drug interactions may interfere with the repair mechanisms or modulate the expression of pulmonary toxicity. […] Pulmonary drug toxicity is increasingly being recognised as a cause of interstitial lung disease (ILD) and, as this lung disorder can be progressive and fatal, early recognition is important.

• #1 Deciphering drug-induced interstitial lung disease: A mechanistic approach | Applied Radiology

  https://appliedradiology.com/articles/deciphering-drug-induced-interstitial-lung-disease-a-mechanistic-approach

  Drug-induced interstitial lung disease (DI-ILD), defined as an interstitial abnormality secondary to administration of a drug, can be acute or chronic. The mechanism of action of toxicity is largely unknown for most drugs and is an active area of research. In general, effects can be attributed to direct cell toxicity, free radical production, alterations in collagen production, or indirect inflammatory mediated events. Understanding these mechanisms can help explain the different imaging patterns of lung toxicity. Diffuse alveolar damage (DAD) is a pathology term that describes the presence of alveolar fibrin, hyaline membranes and reactive epithelial cells within alveoli, with varied stages of inflammation. Drugs that disrupt the alveolus via apoptosis or delay the process of barrier restoration could, therefore, lead to DAD and possibly to fibrosis. Indirect cell toxicity from drug metabolites is another pathway by which DI-ILD may occur. Of particular importance are drugs that produce reactive oxygen species during metabolism. Oxidative stress may cause apoptosis of structural cells making up the interstitium, thus playing a role in fibrosis. Organizing pneumonia (OP) is characterized by plugs of collagen and fibroblasts that fill respiratory bronchioles, alveolar ducts and alveoli. The high lymphocyte count seen in bronchoalveolar lavage (BAL) and the rapid response to steroids suggest that the pathophysiology for organizing pneumonia is immune-related. Pulmonary fibrosis is the result of excessive deposition of extracellular matrix proteins in the lung. Fibroblasts normally maintain matrix homeostasis by modulating the turnover of the extracellular membrane (ECM). Drugs that lead to fibrosis may alter these pathways, favoring the activation of fibroblasts, conferring them with relative resistance to apoptosis or promoting neovascularization that supports ECM remodeling.

• #1 Understanding the mechanisms of drug-associated interstitial lung disease | British Journal of Cancer

  https://www.nature.com/articles/6602065

  The development of ILD associated with anticancer agents is considered to be a multistep process, although one of the key initiating factors is likely to be the apoptosis of non-neoplastic type I and II pneumocytes. […] Mitochondrial-mediated apoptotic pathways, activated in lung tissues from patients with idiopathic interstitial pneumonia, may be involved in the pathophysiology of the disease. […] However, to further understand the mechanisms involved in EGFR inhibition and ILD it would be interesting, through further research, to elucidate the key cell types involved (e.g. type II pneumocytes).

• #1 The pathogenesis of interstitial lung diseases in children – EM consulte

  https://www.em-consulte.com/article/493793/the-pathogenesis-of-interstitial-lung-diseases-in-

  The pathological changes observed in interstitial lung disease (ILD) are characterised by derangements of the alveolar walls. […] The current concept on ILD pathogenesis relies on an epithelial/fibroblastic pathway with epithelial injury and activation, formation of subepithelial fibroblast/myofibroblast foci and excessive accumulation of extracellular matrix. […] An essential step in the restoration of alveolar integrity is the rapid re-epithelialisation of the altered surface, mainly through epithelial proliferation and migration. […] In the context of lung growth and development in paediatric ILD, it is suggested that the programmed production of mitogenic factors may promote the process of re-epithelialisation and may help to counteract the altered secretion of mediators involved in migration and proliferation of fibroblasts and differentiation into myofibroblasts. […] This is supported by clinical observations indicating that paediatric ILD is more responsive to therapeutic strategies than adult ILD.

• #1 The Restrictive Lung Diseases – Pulmonary Pathophysiology for Pre-Clinical Students

  https://pressbooks.lib.vt.edu/pulmonarypathophysiology/chapter/the-restrictive-lung-diseases/

  It is worth noting at this point that some forms of ILD are caused by an exaggerated immune reaction either through an allergic-like response, or a direct immune disorder. […] The action of fibroblasts laying down connective tissue, combined with the destruction of alveolar and capillary structures, leads to a widening of airspaces with thick collagenous and infiltrated walls, which are a functionally significant departure from the ideal structure for gas exchange. […] The thickened basement membrane poses a significant obstacle to the transfer of gases, and the dense connective tissue stiffens the lung and thereby reduces its compliance. […] Combined with loss of capillary beds and airspace surface area, gas exchange is reduced. […] Interstitial inflammation and connective tissue deposition lead to reduced diffusion capacity, hypoxemia, and cor pulmonale.

• #1 The Restrictive Lung Diseases – Pulmonary Pathophysiology for Pre-Clinical Students

  https://pressbooks.lib.vt.edu/pulmonarypathophysiology/chapter/the-restrictive-lung-diseases/

  The reduction in lung compliance leads to a reduced lung volume. […] The reduction in tidal volume, combined with a raised hypoxic drive to breathe, results in the cardinal symptom of ILD, which is dyspnea. […] The presence of lymphocytes in biopsy and bronchoalveolar lavage fluid suggests the involvement of the immune system in the pathogenesis of nonspecific interstitial pneumonia. […] This is supported by the occurrence of NSIP in immune diseases such as HIV infection and several connective tissue disorders including polymyositis, rheumatoid arthritis, and systemic sclerosis. […] The hallmark of COP is an excessive proliferation of granulation tissue made of collagen-embedded fibroblasts and myofibroblasts that starts in the alveolar space. […] The pathogenesis is an initial alveolar injury, with plasma proteins leaking into the alveolar lumen that is followed by recruited fibroblasts depositing connective tissue with the lumen itself. […] The granulomas are indistinguishable from those caused by sarcoidosis, and many CBD patients may be misdiagnosed as sarcoidosis cases, so appropriate history taking is paramount.

• #1 Pathogenesis of interstitial lung disease in systemic sclerosis

  https://www.degruyter.com/document/doi/10.2478/rir-2024-0020/html?lang=en

  There are parallels between SSc-ILD and the overall disease in considering aetiopathogeneses that reflect susceptibility to ILD and triggering events that are likely to be intrinsic to the disease as well as environmental. […] A general schematic summarising the development of SSc-ILD is provided in Figure 1. This integrates likely genetic, environmental and pathobiological aspects of the disease. These determine not only the development of ILD but also its severity and rate of progression. […] Together, these mouse strains have provided powerful insight into the development of SSc-ILD. They suggest that lung injury, including epithelial injury is important especially for persistent progressive lung disease along with immunological mechanisms. […] The notion is that systemic effects of SSc make tissue more susceptible to fibrosis in response to minor injury and that there may be fibroblast-dependent dysregulated connective tissue repair with scarring as a unifying disease mechanism. […] Understanding pathogenesis is important because it links directly to the concept of precision or stratified medicine.

• #1

  https://www.pneumon.org/What-is-new-in-the-treatment-of-interstitial-lung-ndiseases,161867,0,2.html

  Although the precise mechanisms have not been fully elucidated, the exposome and the genome of each individual seem to have a cardinal role in a multiple-hits pathogenic process. […] To this end, the two main treatment regimens in the context of ILDs are anti-inflammatory and antifibrotic compounds. Pharmacological management is driven by lumping ILDs according to the presumptive predominant pathogenic mechanism, although the coexistence of inflammation and fibrosis may be challenging. […] Antifibrotics were initially launched in IPF. However, the term progressive pulmonary fibrosis (PPF) has been recently coined to describe fibrotic lung diseases, other than IPF, that develop into a progressive disease phenotype within a period of 1 year, as defined by clinical, functional and/or radiological parameters.

• #1 Basics of Interstitial Lung Diseases | ILD Collaborative

  https://www.ildcollaborative.org/resources/basics-of-ilds

  Autoimmune disease-related ILD caused by an underlying autoimmune disease, in which the immune system attacks a persons own body tissues. […] An ILD that primarily causes inflammation in the interstitium can be treated by calming the immune system down. Anti-inflammatory drugs, like steroids, or immune suppressant drugs can be used to treat ILDs in this category. […] An ILD that primarily causes fibrosis (scarring) in the interstitium can be treated with anti-fibrotic medications. For example, idiopathic pulmonary fibrosis (IPF) causes fibrosis (scarring) and can be treated with nintedanib or pirfenidone.

• #1

  https://www.pneumon.org/What-is-new-in-the-treatment-of-interstitial-lung-ndiseases,161867,0,2.html

  Based on the fact that pulmonary fibrosis is an end stage situation requiring therapy to hinder disease progression, there has been much interest in whether antifibrotics could be beneficial in PPF. […] The definition of PPF integrates fibrotic ILDs, excluding IPF, that worsen in at least two of the following: respiratory symptoms, functional indices or radiological findings, in twelve months with no alternative explanation. […] Based on the hypothesis that the use of antifibrotics may decelerate PPF worsening, similar to their beneficial effects on IPF, several clinical trials were introduced in order to assess the possible effectiveness of pirfenidone and nintedanib in progressive fibrosis. […] The SENSCIS study reported that nintedanib decreased the rate of FVC decline and the subsequent disease progression in patients with SSc-ILD, although it seemed to have a limited role in other manifestations of SSc. […] According to the results of the INBUILD trial and the new guidelines, treatment with nintedanib is suggested in PFF, when conventional therapies have failed.

• #1 Interstitial lung disease in Systemic sclerosis: insights into pathogenesis and evolving therapies | MJR – Mediterranean Journal of Rheumatology

  https://www.mjrheum.org/september-2018/newsid792/137

  Interstitial lung disease (ILD) is a leading cause of mortality in systemic sclerosis (SSc). […] However, mortality is improving as pathogenesis is being better understood and new therapies emerge. The roles of the inflammasome and NETosis in fibrosis are being elucidated. […] Epigenetic targets like DNA methylation and microRNA show promise as new targets for anti-fibrotic agents. The IL17-23 pathway has been shown to be active in SSc-ILD. […] A plethora of studies has shown the benefit of immunosuppression in halting ILD progression. […] The inflammation in SSc is mostly subclinical and there is great interest in developing anti-fibrotic drugs for SSc-ILD.

• #1 Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease | Inflammation and Regeneration | Full Text

  https://inflammregen.biomedcentral.com/articles/10.1186/s41232-024-00345-2

  There are several drug candidates in clinical development for fibrotic ILD that have novel modes of action. One such mechanistic target is enhanced intracellular signaling by the second messenger cAMP. […] Inhibition of the ATX-LPA axis is another novel therapeutic target in fibrotic ILD. LPA is a phospholipid growth factor that binds to LPA receptors, eliciting diverse downstream functions, whereas ATX is a secreted enzyme that generates the majority of circulating LPA through hydrolysis. […] Knowledge of the pathological mechanisms that drive progressive fibrosis in patients with ILD has expanded, with the role of alveolar endothelial cells, the immune system, and fibroblasts better elucidated due to technological advances in sequencing and multiomic analyses.

• #1 Interstitial Lung Disease Patterns in AAV Affect Prognosis – Renal and Urology News

  https://www.renalandurologynews.com/news/vasculitis-aav-interstitial-lung-disease-patterns-affect-prognosis/

  Interstitial lung disease (ILD) patterns differ between patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV), with potentially wide-ranging prognostic implications, according to a study published in Seminars in Arthritis Rheumatism. […] The researchers found contrasting characteristics between individuals with a typical UIP pattern and those with a non-UIP pattern. […] These differences had an impact on prognosis. Patients with typical UIP had longer survival compared with those with other ILD patterns; this was true at both the 1- and 5-year mark. […] In conclusion, the different ILD patterns in AAV may have different pathophysiology and treatment/prognostic implications, the authors wrote. Additional research is needed to decipher the mechanisms underlying these differences within those with AAV-ILD.

• #1 Interstitial Lung Disease | Division of Rheumatology

  https://rheumatology.uw.edu/patient-care/patient-information-portal/interstitial-lung-disease

  It may not be as responsive to suppressing the immune system as other patterns but there are new medications that are now available that help reduce the progression of scar tissue formation known as antifibrotic therapy. […] Non-specific interstitial pneumonitis (NSIP) this form also affects predominately the lower portions of the lungs and is characterized by GGOs and reticulations. […] Honeycombing is not typically seen in this form of ILD. […] It tends to be more responsive to therapy than a UIP pattern with medications that suppress inflammation. […] Cryptogenic organizing pneumonia (COP) – is sometimes seen in patients who are considered to have interstitial lung disease and areas of consolidation/ fluid accumulation in the small airways that can represent inflammation or even sometimes blood.

• #1 Pathogenesis of interstitial lung disease in systemic sclerosis

  https://www.degruyterbrill.com/document/doi/10.2478/rir-2024-0020/html?lang=en&srsltid=AfmBOorGcXIkDZU0H6LLElpTBnAAXJD09rgIFCRqufkGMf_R3C9nu6YI

  A general schematic summarising the development of SSc-ILD is provided in Figure 1. This integrates likely genetic, environmental and pathobiological aspects of the disease. These determine not only the development of ILD but also its severity and rate of progression. […] Together, these mouse strains have provided powerful insight into the development of SSc-ILD. They suggest that lung injury, including epithelial injury is important especially for persistent progressive lung disease along with immunological mechanisms. […] The notion is that systemic effects of SSc make tissue more susceptible to fibrosis in response to minor injury and that there may be fibroblast-dependent dysregulated connective tissue repair with scarring as a unifying disease mechanism. […] Understanding pathogenesis is important because it links directly to the concept of precision or stratified medicine. […] Identifying these high-risk cases may offer new opportunities for prevention of lung fibrosis.

• #2 Frontiers | Interstitial lung disease: a review of classification, etiology, epidemiology, clinical diagnosis, pharmacological and non-pharmacological treatment

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1296890/full

  Interstitial lung diseases (ILDs) refer to a heterogeneous and complex group of conditions characterized by inflammation, fibrosis, or both, in the interstitium of the lungs. This results in impaired gas exchange, leading to a worsening of respiratory symptoms and a decline in lung function. […] While the etiology of some ILDs is unclear, most cases can be traced back to factors such as genetic predispositions, environmental exposures (including allergens, toxins, and air pollution), underlying autoimmune diseases, or the use of certain medications. […] The development of these cases is a complex process that is influenced by a variety of factors, including the individual’s genetic traits, and exposure to environmental pollutants. […] The purpose of this review is to provide up-to-date information on interstitial lung disease (ILD), with a particular emphasis on definition, classifications, etiology, epidemiology, diagnosis, pharmacological, and non-pharmacological management.

• #2 Interstitial lung disease – Wikipedia

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

  Interstitial lung disease (ILD), or diffuse parenchymal lung disease (DPLD), is a group of respiratory diseases affecting the interstitium (the tissue) and space around the alveoli (air sacs) of the lungs. It concerns alveolar epithelium, pulmonary capillary endothelium, basement membrane, and perivascular and perilymphatic tissues. It may occur when an injury to the lungs triggers an abnormal healing response. Ordinarily, the body generates just the right amount of tissue to repair damage, but in interstitial lung disease, the repair process is disrupted, and the tissue around the air sacs (alveoli) becomes scarred and thickened. This makes it more difficult for oxygen to pass into the bloodstream. […] In children, the pathophysiology involves a genetic component, exposure-related injury, autoimmune dysregulation, or all of the components.

• #2 Frontiers | Interstitial lung disease: a review of classification, etiology, epidemiology, clinical diagnosis, pharmacological and non-pharmacological treatment

  https://www.frontiersin.org/journals/medicine/articles/10.3389/fmed.2024.1296890/full

  While the pathophysiological mechanisms are not entirely understood, ILD is categorized as a restrictive lung disease that reduces lung expansion and total lung capacity. […] Scarring and lung damage are linked to the creation of fibroblastic foci, where fibroblasts proliferate in response to alveolar cell injury. Triggered by transforming growth factor beta (TGF-β), this process transforms fibroblasts into myofibroblasts, which secrete collagen, leading to fibrosis. […] The inflammatory response is a complex cascade of events involving various immune cells, such as lymphocytes and macrophages, as well as the release of inflammatory mediators like cytokines and chemokines. […] However, in the case of interstitial lung disease (ILD), the inflammatory process becomes dysregulated and can lead to progressive lung damage. […] The persistent inflammation leads to further tissue damage, creating a vicious cycle. […] Abnormal multiplication and excessive protein secretion by fibroblasts, including collagen, contribute to the process of fibrosis.

• #2 Pathological mechanisms and novel drug targets in fibrotic interstitial lung disease | Inflammation and Regeneration | Full Text

  https://inflammregen.biomedcentral.com/articles/10.1186/s41232-024-00345-2

  Although fibrosis is a normal physiological response that occurs as part of wound healing and host defense against pathogens, this process can malfunction, causing exaggerated pro-inflammatory and profibrotic responses. This leads to fibroblast activation and differentiation into myofibroblasts, extracellular matrix (ECM) deposition, and remodeling of the functional lung tissue, resulting in tissue stiffness and compromised gaseous exchange. […] The initial triggers of fibrotic ILD can be broadly categorized into two types: epithelial cell injury, as is the case of IIPs such as IPF, and immune activation, which can result from autoimmune disease or exposure to a persistent antigen. […] Epithelial cell injury is an important initial step in the progression of lung fibrosis, particularly in IPF, and has multiple potential triggers, including environmental exposure from smoking, occupational hazards, air pollution, and viruses.

• #2 Interstitial Lung Disease | Division of Rheumatology

  https://rheumatology.uw.edu/patient-care/patient-information-portal/interstitial-lung-disease

  Interstitial lung diseases are felt to result from an overreaction of the repair mechanisms in the lung tissue. […] There is an overabundance of fibroblasts or cells that cause scar tissue produced in the lungs in response to inflammatory chemicals such as transforming growth factor beta (TGF beta), platelet drive growth factor (PDGF), and fibroblast growth factor (FGF). […] The end result is that the normal thin lung tissue that acts as a membrane to help transfer oxygen from the lungs into the bloodstream is thickened by scar tissue and can no longer serve its normal purpose. […] Usual interstitial pneumonia (UIP) This form of interstitial lung disease typically involves the lower portions of the lung and is characterized by the presence of reticulations, traction bronchiectasis, and honeycombing.

• #2 Pathogenic pathways to fibrogenesis | PulmonaryFibrosis360.com

  https://www.pulmonaryfibrosis360.com/rheums/ra-ild/common-pathophysiology-of-fibrotic-ctd-ilds

  Based on the pathogenesis of fibrotic interstitial lung disease in connective tissue diseases, a new treatment paradigm of CTD-ILDs suggests to not only target inflammation but also fibrosis. […] A complex interplay of inflammatory, fibrotic and vascular processes leads to the activation and proliferation of fibroblasts, their differentiation into myofibroblasts, and the excessive secretion of extracellular matrix. […] Irrespective of the clinical diagnosis, there are commonalities in the underlying pathogenetic mechanisms that drive a self-sustaining process of pulmonary fibrosis. […] Once pulmonary fibrosis has become self-sustaining, fibroblasts can become partially independent of external stimulation and the initiating inflammatory response. […] Progressive fibrosing CTD-ILDs are driven by a common pathophysiology.

• #2 Understanding the mechanisms of drug-associated interstitial lung disease | British Journal of Cancer

  https://www.nature.com/articles/6602065

  Although the mechanisms by which lung fibrosis develops are not fully understood, recent findings suggest that oxidative stress may play an important role in the pathogenesis of tissue fibrosis affecting apoptosis of both structural and inflammatory cells and altering the cytokine microenvironment balance. […] Increased production of transforming growth factor beta (TGF-β) was demonstrated in epithelial cells of terminal airways and alveoli in idiopathic pulmonary fibrosis. […] In addition to multiple effects on the process of fibrogenesis, TGF-β1 can induce apoptosis in various cells. […] The mechanism of TGF-β1-mediated apoptosis probably varies among cell types. […] TGF-β1 is a potent inducer of apoptosis through caspase-3 activation and the downregulation of p21. […] It is also an enhancer of Fas-mediated apoptosis of lung epithelial cells.

• #2 Interstitial Lung Diseases and Non-Small Cell Lung Cancer: Particularities in Pathogenesis and Expression of Driver Mutations

  https://www.mdpi.com/2073-4425/15/7/934

  Interstitial lung diseases (ILD) constitute a heterogenous group of chronic lung diseases, characterized by inflammation and fibrosis. The pathogenesis of IPF is a complex process that includes responses to epithelial damage and several molecular mechanisms that lead to fibrosis. The recurrent alveolar epithelial cell (AEC) injury model is the main pathogenetic mechanism that is described. Predisposing factors, such as genetic, environmental, epigenetic, and immunologic, cause epithelial damage and dysregulated epithelial repair. This results in abnormal fibroblast proliferation, dilatation of the extracellular matrix, and loss of normal lung architecture. The molecular events that lead to IPF orchestrate all cell types that participate in epithelial injury repair and lung fibrosis (alveolar epithelial cells, fibroblasts, endothelial cells, and immune cells). Data from scRNA-seq comparing IPF and control lung tissue have provided evidence for the presence of an aberrant epithelial cell type, which expresses markers including matrix metalloproteinase 7 (MMP7), integrin αVβ6, cellular senescence, and epithelial–mesenchymal transition (EMT) and represents a major driver of IPF pathogenesis. IL-1β is important in the normal differentiation of AT2 cells into AT1 cells. IL-1β signaling is another mechanism by which chronic inflammation leads to fibrosis. The Wnt signaling pathway and its nuclear mediator β-catenin are involved in the development of normal lung tissue and organogenesis. It plays a crucial role in the differentiation of the normal bronchial and alveolar epithelial cells. The Wnt pathway is implicated in the pathogenesis of pulmonary fibrosis. After injury, fibroblasts maintain AT2 cells through Wnt signaling. Sustained Wnt signaling through β-catenin inhibits AT2 cell differentiation and leads to lung fibrosis. AT2 cells prevail in the expression of IL-1β and cause fibrosis through TGF-β. It is also described the role of β-catenin signaling in the epithelial–mesenchymal transition (EMT), which is important in embryonic development, tumor progression, and fibrosis. Epithelial–mesenchymal transition (EMT) is a step in normal injury repair and is characterized by the loss of cell-to-cell adhesion molecules, such as E-cadherin and is regulated in IPF and cancer. EMT is probably a process where epithelial cells differentiate into mesenchymal cells and promote local fibrosis. Transforming growth factor-β (TGF-β) is the factor that has a role in fibrosis. In normal healing after injury, fibroblasts, differentiation of myofibroblasts, and deposition of extracellular matrix take place in order to close the trauma. Upregulation of the TGF-β signaling pathway is observed in fibrotic diseases, which promotes activation of fibrotic mesenchymal cells and deposition of extracellular matrix. TGF-β signaling has been involved in pulmonary fibrosis. TGF-β1 activates HMGB1, RELM-β, Slit2, and Fstl1 by cooperating with Smad2 and Smad3 and influences the three steps of idiopathic pulmonary fibrosis (EMT, myofibroblast differentiation, and fibrogenesis). Familiar pulmonary fibroses represent about 5–20% of cases with IPF. This fact suggests that molecular events are implicated in the pathogenesis of the disease. The most common mutation is the MUC5B risk allele. The MUC5B promoter polymorphism is related to mucociliary clearance epithelial activity and is associated with interstitial lung disease. Overexpression of MUC5B leads to mucus hypersecretion in bronchoalveolar epithelium and promotes inflammation and injury. Toll-interacting protein is an intracellular adaptor protein that has a role in inflammation, immune response, and lung epithelial cell apoptosis. Polymorphism in the promoter for the Toll-interacting protein (TOLLIP) is another genetic event that is associated with an increased risk of developing IPF. These genetic variants provide novel advantages for targeted therapies in IPF. Telomeres are nucleotide sequences that stabilize chromosome edges in order to prevent chromosome shortening during cell replication. Telomerase-related mutations (TRM) are observed in familiar and sporadic IPF. Several mutations of this protein complex have been described, with TERC and TERT being the most common. Patients with ILD have an increased risk of developing lung cancer. In a metanalysis of 35 studies, 13.5% of patients with IPF developed non-small cell lung cancer (NSCLC). There are several common molecular events that are observed in lung cancer and in patients with ILD. Mutations in the TP53 gene have been found in patients with squamous cell carcinoma of the lung and IPF. Decreased PTEN expression and hyperactivation of Akt have been discovered in the alveolar epithelial cells and fibroblastic areas of human IPF lungs and patients with lung cancer. That makes PTEN/P13K/Akt signaling a crucial pathogenetic mechanism and a potential therapeutic target for IPF and NSCLC. Cancer-associated fibroblasts (CAFs) are specific cell types that determine tumors biological behavior. These results suggest the need for more research to discover the mechanisms linking pulmonary fibrosis and lung carcinogenesis. The treatment of patients with IPF and lung cancer is challenging because surgery, radiation therapy, or chemotherapy may cause exacerbations of the underlying ILD, which can lead to complications and death. Thus, it is important to find targeted therapies with fewer complications for these patients in order to decrease morbidity and mortality.

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

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

  Despite the comprehensive understanding of IPF pathogenesis remains elusive, research efforts in the last few years have reached important milestones. […] The main pathogenetic actors in IPF are also illustrated in Fig. 1. […] 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 repetitive exposure of alveolar epithelium to microinjuries, as infections, cigarette smoke, environmental inhaled toxics, gastro-oesophageal reflux lead to damage of AEC1s. […] The cellular activity leads to protein over-expression and endoplasmic reticulum stress (ERS), a protective pathway that occurs when there is an imbalance between cellular demand for protein synthesis and the endoplasmic reticulum capacity to work properly.

• #2 Interstitial Lung Disease | Thoracic Key

  https://thoracickey.com/interstitial-lung-disease-3/

  Studies have revealed an association between short telomere length and idiopathic pulmonary fibrosis (IPF); these findings are consistent with the increased prevalence of IPF in elderly patients and implicate accelerated cellular aging or stem cell exhaustion as additional mechanisms of disease in some ILDs.

Zobacz więcej