Materiały źródłowe

• #1 Silicosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK594245/

  Silicosis, a type of pneumoconiosis, occurs secondary to the inhalation of RCS and causes progressive, irreversible, and fatal lung inflammation and fibrosis. […] Long-term occupational exposure to RCS is associated with the development of silicosis, a devastating interstitial lung disease characterized by diffuse pulmonary fibrosis. […] RCS particles are small enough to bypass the pulmonary mucociliary defense system and into the terminal airways and alveoli, where they are coated with pulmonary surfactant. […] In response to immune stimulation by the silica particles, alveolar macrophages influence alveolar type II cells and bronchiolar epithelial cells to produce a copious amount of surfactant. […] The sustained overproduction of surfactant and the accumulation of the denatured protein is an acute pathological feature of silica exposure.

• #1 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8072896/

  Inhalation of silica particles is an environmental and occupational cause of silicosis, a type of pneumoconiosis. Development of the lung silicosis is a unique process in which the vicious cycle of ingestion of inhaled silica particles by alveolar macrophages and their release triggers inflammation, generation of nodular lesions, and irreversible fibrosis. The pathophysiology of silicosis is complex, and interactions between the pathomechanisms have not been completely understood. However, elucidation of silica-induced inflammation cascades and inflammation-fibrosis relations has uncovered several novel possibilities of therapeutic targeting. […] The background of pathological changes in silica-injured lungs is complex and not completely understood. Silica-induced lung injury presumably results from the combined action of several interacting pathomechanisms, such as the direct cytotoxic effect of silica on macrophages, activation of macrophage surface receptors, lysosomal rupture, production of reactive oxygen species (ROS), activation of inflammasome, production of cytokines and chemokines, cell apoptosis/pyroptosis, and lung fibrosis.

• #1 Silicosis – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK594245/

  Macrophages collect at damaged pulmonary tissue, stimulating the activity of fibroblasts, leading to pulmonary fibrosis, formation of silicotic nodules, and reduction of lung area available for gas exchange. […] The silica particles released by macrophage destruction are either excreted via the mucociliary escalator, transported through lymphatic drainage, or engulfed by other alveolar macrophages, stimulating a vicious cycle of cellular destruction, inflammation, and pulmonary damage. […] These pathologic changes are much more indolent than the abrupt silicoproteinosis experienced in voluminous acute exposures.

• #1 Silicosis – Wikipedia

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

  Silicosis is a form of occupational lung disease caused by inhalation of crystalline silica dust. It is marked by inflammation and scarring in the form of nodular lesions in the upper lobes of the lungs. […] When fine particles of crystalline silica dust are deposited in the lungs, macrophages that ingest the dust particles will set off an inflammatory response by releasing tumor necrosis factors, interleukin-1, leukotriene B4 and other cytokines. In turn, these stimulate fibroblasts to proliferate and produce collagen around the silica particle, thus resulting in fibrosis and the formation of the nodular lesions. The inflammatory effects of crystalline silica are apparently mediated by the NLRP3 inflammasome. […] Characteristic lung tissue pathology in nodular silicosis consists of fibrotic nodules with concentric „onion-skinned” arrangement of collagen fibers, central hyalinization, and a cellular peripheral zone, with lightly birefringent particles seen under polarized light. The silicotic nodule represents a specific tissue response to crystalline silica.

• #1 Silicosis: biomarkers and pathogenesis – MedCrave online

  https://medcraveonline.com/JLPRR/silicosis-biomarkers-and-pathogenesis.html

  When the silica particles of 0.5 to 5microns in diameter are inspired into the lungs, these particles get embedded into the alveolar sacs and ducts and cause inflammation. The inflammation and scarring damage the pulmonary alveolar sacs, prevent gas exchange in the lungs, and contribute to abnormal breathing. The damage to the lung tissue leads to reduction of oxygen supply to the blood. Silicosis is an irreversible medical condition without cure. Degree of silica-dust exposure is directly associated with occurrence of silicosis. […] How silica particles stimulate pulmonary response and the precise pathophysiology of silicosis are still research questions. Nevertheless, several studies indicated interactions between respirable silica particles and pulmonary alveolar macrophages and this interaction plays major role in the development of the silicosis disease. The intensity of the inhaled silica particles influence on the nature and extent of the pulmonary alveolar response that provides explanation to some silicosis extension why rock drillers and sandblasters who are intensively exposed to freshy fractured silica dust develop silicosis disease.

• #1 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://www.mdpi.com/1422-0067/22/8/4162

  Although the molecular mechanisms of silica-induced inflammation, fibrosis, and the related autoimmune responses have not been completely understood yet, there has been a generally accepted concept supporting the contribution of inflammation in the development of fibrosis and autoimmune responses due to silica inhalation. […] Activation of the inflammatory pathways, including inflammasome and NF-κB, due to exposure to silica particles leads to increased production of pro-inflammatory cytokines. Among them, elevated levels of IL-1β, IL-18, and tumor necrosis factor (TNF)α are strongly associated with the development of lung fibrosis as they stimulate the recruitment of fibroblasts and the proliferation of fibroblasts and mesenchymal cells to form fibroblastic foci, as well as releasing high amounts of components of the extracellular matrix, including collagen, fibronectin, hyaluronic acid, and proteoglycans.

• #1 The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

  https://www.mdpi.com/1422-0067/22/15/8110

  Silicosis remains one of the most severe pulmonary fibrotic diseases worldwide, caused by chronic exposure to silica dust. […] Programmed cell death (PCD), including autophagy, apoptosis, and pyroptosis, is closely associated with silicosis progression. […] Silicosis pathogenesis depends on the crosstalk among these three ways of PCD to a certain extent. […] The current widely accepted silicosis pathogenesis is as follows: (1) Silica is identified and then phagocytosed by the alveolar macrophage (AM) via the scavenger receptor, which is the first critical defensive line for silica invasion. […] Silicosis is developed through a vicious circle. AM engulfs silica to cause AM death and then releases intracellular silica that is further taken up by other AMs. […] Silicic acid produced by dissolved silica destroys the stability of the AM lysosomal membrane.

• #1 Silicosis – Pulmonary Disorders – Merck Manual Professional Edition

  https://www.merckmanuals.com/professional/pulmonary-disorders/environmental-and-occupational-pulmonary-diseases/silicosis

  In low-intensity or short-term exposures, these nodules remain discrete and do not compromise lung function (simple chronic silicosis). With higher-intensity or more prolonged exposures (complicated chronic silicosis), these nodules coalesce and cause progressive fibrosis and restrictive lung dysfunction, or they sometimes form large conglomerate masses (called progressive massive fibrosis).

• #1 BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis | Cell Death & Disease

  https://www.nature.com/articles/cddis201778

  Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. […] The role of BBC3/PUMA (BCL2-binding component 3) in macrophages during silicosis remains unknown. […] We found that SiO2 induced increased BBC3 expression, as well as macrophage activation and apoptosis. […] Knockdown of Bbc3 with specific siRNA significantly mitigated the SiO2-induced effects. […] Our results clearly showed increased levels of autophagy in macrophages exposed to SiO2. […] However, inhibition of BBC3 decreased the occurrence of autophagy. […] Furthermore, we observed that the blockade of autophagy with 3-MA, an autophagy inhibitor, inhibited SiO2-induced macrophage activation and apoptosis. […] In contrast, rapamycin, an autophagy inducer, further enhanced the effects induced by SiO2.

• #1 The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

  https://www.mdpi.com/1422-0067/22/15/8110

  The apoptosis occurring at an early stage of the silicosis progression has a compensatory function to clear up injured cells and inflammation, assisting in the lung tissue remodeling. […] When AM has a failed phagocytosis or abnormalities in the clearance of the apoptotic AMs, the level of AM apoptosis will escalate gradually, aggravating silicotic fibrosis eventually. […] Recent evidence suggests that silica may also be a “red flag” for stimulating cell pyroptosis on a pathological level. […] The crosstalk that exists between autophagy and apoptosis. […] The degree of the blockade of autophagic degradation, not autophagy activity, may reflect positive or negative effects of autophagy on silicosis better when discussing the function of the exogenous toxic substance or potential protective agent on silica-induced autophagy.

• #1 The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

  https://www.mdpi.com/1422-0067/22/15/8110

  Dead AMs can release a series of inflammatory factors, causing pulmonary inflammatory damage. […] These steps are not necessarily executed in order or parallel strictly, and they are interspersed and connected to cause silicotic fibrosis. […] The inhibited activity of autophagy has been observed in TGF-β-treated fibroblasts. […] Their over-expression alleviated both the distribution and severity of lung lesions. […] Overall, unlike AM, related research based on silica-activated fibroblasts or myofibroblasts should promote autophagy or apoptosis to seek promising intervention methods of silicosis. […] Silica has been proven to regulate autophagy activity via the phosphatidylinositol 3 kinase (PI3K)/protein kinase B (PKB/Akt)/mammalian target of rapamycin (mTOR) signaling pathway. […] The basic autophagy level has a compensatory protective function for silica invasion; however, cells seem to have the ability to sense the stress caused by silica, which further leads to dysregulation of related signaling pathways and even cell death via the abnormal occurrence of autophagy.

• #1 The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

  https://www.mdpi.com/1422-0067/22/15/8110

  Silicotic progression depends on the combined effect of silica and exogenous irritants, not silica alone. […] Pyroptosis may be a potential mechanism during the development of silicosis, and it should also be regarded as an “outcome variable” to assess the severity of pathological changes in silicosis.

• #1 Crystalline silica-induced recruitment and immuno-imbalance of CD4+ tissue resident memory T cells promote silicosis progression | Communications Biology

  https://www.nature.com/articles/s42003-024-06662-z

  Occupational crystalline silica (CS) particle exposure leads to silicosis. […] Here we show that pulmonary CD4+ tissue-resident memory T cells (TRM) accumulate in response to CS particles, mediating the pathogenesis of silicosis. […] The inhaled CS particles deposited in the lung interstitium trigger inflammatory cascades involving innate and adaptive immune responses. […] Different from the simple exposure-response relationship, adaptive immune response characterized as disorders of T lymphocytes orchestrate chronic inflammation and fibrogenesis. […] CD4+ helper T (Th) cells have been identified as vital players in fibrotic disorders, including silicosis. […] Notably, T cell-mediated adaptive immune response is characterized as immunological memory. […] In the pathogenesis of silicosis, the inhaled CS particles can be engulfed by macrophages but cannot be cleared, resulting in the re-release of CS particles, which leads to repeatedly, locally re-initiated chronic inflammation.

• #1 Crystalline silica-induced recruitment and immuno-imbalance of CD4+ tissue resident memory T cells promote silicosis progression | Communications Biology

  https://www.nature.com/articles/s42003-024-06662-z

  Given the situation of repeated CS stimulation and the immunologic memory function of TRM cells, we hypothesized that CD4+ TRM cells are involved in the pathogenesis of silicosis. […] Our results demonstrated CS particles induced substantial accumulations of pulmonary CD4+ TRM cells. […] The CD69+CD103 CD4+ TRM subset manifested robust pro-inflammatory responses, whereas the CD69+CD103+ CD4+ TRM subset was immuno-suppressive. […] Significantly, targeting the maintenance and function of pathogenic lung CD4+ TRM cells exerted protective effects against silicosis. […] CD4+ TRM cells exerted immuno-memory to the CS particles mediated the pathogenesis of silicosis, and the CD69+CD103 TRM subsets possessed robust pathogenic capacity to silicosis. […] Collectively, these results demonstrated that targeting CD103+ TRM cells could not mitigate CS-induced pulmonary fibrosis, which was related to the expansion of TRM-Teff cells.

• #1 Silicosis: biomarkers and pathogenesis – MedCrave online

  https://medcraveonline.com/JLPRR/silicosis-biomarkers-and-pathogenesis.html

  Several studies revealed that silica promote macrophage activation. The affected macrophages release inflammatory mediators and chemotactic factors that trigger cellular responses of the leukocytes and lymphocytes and then release the fibroblast stimulating factor. Hyalinization and collagen deposition are promoted by the fibroblast stimulating factor and resulting in pathologically pulmonary nodular lesion. This pulmonary nodule composes of a central acellular zone with free silica and surrounding spirals of collagen and fibroblasts. […] After ingestion of silica particles, pulmonary alveolar macrophages secrete fibroblast-stimulating factor. Then macrophages die due to the toxicity of the ingested silica and these silica particles are re-ingested by macrophages and this process is progressively magnified. Lysosomal enzymes are then released rapidly into the cytosol and contributing breakdown of the intracellular organelles with irreversible injury to the affected pulmonary alveolar cells. Intracellular lysosomal rupture circumstantially results in cell death. It seems that damage of the plasma membrane results in macrophage death. Nevertheless, pathogenesis of silicosis may be associated with immunological mechanism due to identification of abnormal serum immunoglobulins and immunoglobulins in the silicotic nodules.

• #1

  https://journals.lww.com/co-allergy/fulltext/2024/04000/association_between_silicosis_and_autoimmune.2.aspx

  This cytokine inflammatory status induced by exposure to silica upregulates airway hyperreactivity and elevated antinuclear antibody levels in a bronchoalveolar lavage fluid in in a NOD/ShiLtJ mice exposed to silica. […] A rapid onset of autoimmune disease pathogenesis was achieved using female lupus-prone NZBWF1 mice. After 7 days after instillation of silica particles, it was shown that there was a robust recruitment of macrophages, neutrophils, and lymphocytes into the alveoli, cell death reflected by increased protein, double-stranded DNA, and lactate dehydrogenase activity, elevated secretion of the cytokines interleukin (IL)-1, IL-1, IL-18, TNF-, IL-6, MCP-1, B cell activation factor (BAFF) and upregulation of genes associated with chemokines, proinflammatory cytokines. […] In a human in vitro study using peripheral blood mononuclear from workers with moderate to high exposure level to silica, it was found that exposure was associated with a decrease of Tregs (CD4+CD25+CD127FoxP3+) compared to controls. Serum autoantibody detection was significantly higher in exposed workers (10 years) compared controls. Antinuclear antibodies and ANCA were detected in 44% and 22% among expose workers as compared to 5% and 2.5% controls. This may be the mechanism of tolerance breakdown against to auto-antigens.

• #1 The Role of Fibrocyte in the Pathogenesis of Silicosis – ADS

  https://ui.adsabs.harvard.edu/abs/2018BioES..31..311L/abstract

  Exposure to free silica induces silicosis and myofibroblasts are regarded as primary effector cells. […] Fibrocytes can differentiate into myofibroblast. […] Results showed that fibrocytes participate in silicosis. […] Trend analysis of different sources of myofibroblasts during silicosis indicated that fibrocytes and lung type II epithelial cell-derived myofibroblasts play an important role in the early stage of silicosis, while resident lung fibroblast-derived myofibroblasts play a predominant role during the fibrosis formative period.

• #1 Anti‑fibrotic effects and the mechanism of action of miR‑29c in silicosis

  https://www.spandidos-publications.com/10.3892/mmr.2021.11932

  Silicosis is an occupational disease caused by the inhalation of free silica dust, and is characterized by diffuse fibrosis in the lung tissue. […] The exact mechanisms contributing to the pathogenesis of pulmonary silicosis remain unclear, limiting the scope for the development of targeted therapies for this disease. Nonetheless, it is generally considered that alveolar macrophages and lung fibroblasts are the main target and effector cells contributing to the fibrosis that underlies silicosis. […] While the critical factors involved in the pathogenesis of silicosis have yet to be fully elucidated, accumulating evidence indicates that TGF- (6), collagen type I I (COL11) (6), COL31 (7) and -smooth muscle actin (-SMA) (8) serve important roles in the process of pulmonary fibrosis. […] The present study aimed to examine the role and mechanism of action of miR-29c in the pathogenesis of silicosis and the associated fibrotic process.

• #1 Anti‑fibrotic effects and the mechanism of action of miR‑29c in silicosis

  https://www.spandidos-publications.com/10.3892/mmr.2021.11932

  The pathogenesis of silica dust-induced pulmonary fibrosis involves a complicated network of biological processes that include inflammation, immunological changes, cell cytotoxicity and tissue repair, as well as a variety of cell types and bioactive substances. […] The current research has indicated that TGF-1 mRNA was upregulated in response to miR-29c inhibition, and downregulated following miR-29c overexpression. The present study concluded that miR-29c can inhibit the fibrotic process that underlies silicosis via its impact on TGF- signaling. […] The present study demonstrated that miR-29c expression was significantly decreased in in vivo and in vitro models of silicosis. It was identified that COL11, COL31, TGF-1 and -SMA, which are key fibrosis-related proteins, were regulated by miR-29c expression. miR-29c expression not only inhibited the expression of a variety of ECM proteins, but it also suppressed the TGF- signaling pathway, which is closely associated with fibrosis.

• #1 Silicosis is on the rise, but is there a therapeutic target? | CNRS

  https://www.cnrs.fr/en/press/silicosis-rise-there-therapeutic-target

  Researchers from the CNRS, the University of Orlans, and the company Artimmune, in collaboration with Turkish clinicians from Atatrk University, have identified a key mechanism of lung inflammation induced by silica exposure, which leads to silicosis, an incurable disease. Their study in mice and patients, published in Nature Communications (December 6th, 2018), shows that this inflammation can be prevented by extracellular DNA degradation, suggesting a new therapeutic target. […] In mice exposed to silica, the researchers showed that DNA released into the airways upon cell death activates a signaling cascade known as the STING pathway. This pathway triggers lung inflammation that ultimately may develop into silicosis. They also demonstrated that treatment with DNase I, an enzyme that degrades the DNA released into the airways, prevents silica-induced lung inflammation. […] Thus the mechanism discovered in mice exposed to silica seems to also play a role in humans. The scientists findings suggest that DNase I, already used in the treatment of other pathologies such as cystic fibrosis, might help patients exposed to silica.

• #1 Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case–control study | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-021-01462-1

  Silicosis is a progressive pneumoconiosis characterized by interstitial fibrosis following exposure to silica dust. The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. […] The repeated process of phagocytosis, necrosis and rephagocytosis of the cells induces inflammation and activation of the reactive oxygen species system, which is associated with pulmonary interstitial fibrosis. […] The role of metabolic dysregulation in the pathogenesis of silicosis has not been investigated in detail. […] Sphingolipid metabolism was the major metabolic pathway in the DEWs, and arginine and proline metabolism was associated with silicosis. […] Distinct metabolic features in the plasma of DEWs and the patients with silicosis were found to be different. Sphingolipid metabolism and arginine and proline metabolism were identified as the major metabolic pathway in the DEW and silicosis groups, respectively.

• #1 Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case–control study | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-021-01462-1

  In the present study, the distinct metabolic features in the plasma of the patients of silicosis compared with that of DEWs were identified to be different. […] In the late pathogenesis of silicosis, the formation of silicotic nodules is the pathological manifestation of the production of collagen fibres and pulmonary interstitial fibrosis mediated by amino acid metabolism, which is consistent with the finding in the present study that arginine and proline metabolism was the major metabolic pathway in silicosis. […] Our data has shown that the plasma level of l-arginine in silicosis was significantly higher than that in the controls and was related to the decline of pulmonary function. […] The present study provided important information regarding sphingolipid metabolism and arginine and proline metabolism in DEWs and patients with silicosis, respectively.

• #1 Treatment Drugs for Silicosis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/45514

  Silicosis, characterized by irreversible pulmonary fibrosis, remains a major global public health problem. Cumulative studies are focusing on elucidating the pathogenesis of silicosis in order to identify preventive or therapeutic antifibrotic agents. […] The pathogenesis of silicosis is not fully understood, and the disease is complex. Although further research is required to clarify the role of intricate signaling pathways, multiple pathways are thought to be involved in the development of silicosis. Silica-induced lung injury is characterized by various mechanisms, including direct cytotoxic effects on macrophages, activation of macrophage surface receptors, lysosomal rupture, reactive oxygen species (ROS) production, inflammasome activation, cytokine and chemokine production, apoptosis/softening, and lung fibrosis.

• #2 Silicosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/302027-overview

  Respirable silica particles ( 10 m in diameter) are deposited within the distal airways and alveoli following inhalation. These particles are then phagocytized by macrophages. Several proinflammatory and profibrotic pathways are then activated, as follows: Interleukin (IL)-1 is stimulated directly by macrophages and indirectly by toll-like receptors. This enhances the production of IL-1, tumor necrosis factor (TNF), caspase-1, and fibroblast growth factor (FGF). […] Subsequent exposure and ingestion of silica by alveolar macrophages leads to cell necrosis, autophagy, and the release of nondegraded intracellular silica. Thus, more macrophages are attracted, causing further release of cytotoxic oxidants and proteases, inflammatory cytokines, and arachidonic metabolites. This vicious cycle self-perpetuates, causing progressive alveolar inflammation and fibrosis.

• #2 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://www.mdpi.com/1422-0067/22/8/4162

  Silica particles are recognized by receptors localized on the surface of alveolar macrophages. Among all classes of scavenger receptors (SR), transmembrane proteins SR-AI, SR-AII and macrophage receptors with a collagenous structure (MARCO) are most associated with silica binding. […] Respirable silica particles (<10 μm), which pass through a mucociliary defence mechanism, may reach distal lung compartments where they initiate a cascade of actions, leading to the development of lung silicosis. In the terminal airways and alveoli, the inhaled silica is engulfed by alveolar macrophages, which are primarily responsible for clearing the lung from debris. However, silica is extremely toxic for macrophages. [...] The cytotoxicity of silica particles may be explained by several hypotheses. Crystalline silica (quartz, cristoballite, and some forms of tridymite) are inherently piezoelectric, i.e., they generate opposite electric charges on opposite sides of the physical structure during the application of pressure. These piezoelectric properties of the crystals, particularly of those freshly fractured, trigger the generation of ROS.

• #2 Silicosis: Background, Pathophysiology, Epidemiology

  https://emedicine.medscape.com/article/302027-overview

  Excess collagen and fibronectin are constantly produced due to activation and recruitment of type II pneumocytes and fibroblast. […] The structure of crystalline silica produces opposite electric charges on opposite sides of the physical structure when pressure is applied onto the crystal. This property is called peizoelectric, which causes the formation of reactive oxygen species when exposed to airways and alveoli. […] Silica-induced oxidative stress stimulates specific transcription factors through interaction with toll-like receptors on alveolar macrophages, mediated through nuclear factor kappa-B (NF-B) and activator protein (AP)-1, which further increases cytokine expression, inducing inflammation and fibrosis.

• #2 Silicosis: biomarkers and pathogenesis – MedCrave online

  https://medcraveonline.com/JLPRR/silicosis-biomarkers-and-pathogenesis.html

  Several studies revealed that silica promote macrophage activation. The affected macrophages release inflammatory mediators and chemotactic factors that trigger cellular responses of the leukocytes and lymphocytes and then release the fibroblast stimulating factor. Hyalinization and collagen deposition are promoted by the fibroblast stimulating factor and resulting in pathologically pulmonary nodular lesion. This pulmonary nodule composes of a central acellular zone with free silica and surrounding spirals of collagen and fibroblasts. […] After ingestion of silica particles, pulmonary alveolar macrophages secrete fibroblast-stimulating factor. Then macrophages die due to the toxicity of the ingested silica and these silica particles are re-ingested by macrophages and this process is progressively magnified. Lysosomal enzymes are then released rapidly into the cytosol and contributing breakdown of the intracellular organelles with irreversible injury to the affected pulmonary alveolar cells. Intracellular lysosomal rupture circumstantially results in cell death. It seems that damage of the plasma membrane results in macrophage death. Nevertheless, pathogenesis of silicosis may be associated with immunological mechanism due to identification of abnormal serum immunoglobulins and immunoglobulins in the silicotic nodules.

• #2 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8072896/

  Silica-induced activation of inflammasome is a fundamental pathway leading to lung injury. […] In silica-induced lung inflammation and injury, NLRP3 inflammasome is of fundamental importance. […] Activation of the inflammatory pathways, including inflammasome and NF-B, due to exposure to silica particles leads to increased production of pro-inflammatory cytokines. Among them, elevated levels of IL-1, IL-18, and tumor necrosis factor (TNF) are strongly associated with the development of lung fibrosis as they stimulate the recruitment of fibroblasts and the proliferation of fibroblasts and mesenchymal cells to form fibroblastic foci, as well as releasing high amounts of components of the extracellular matrix, including collagen, fibronectin, hyaluronic acid, and proteoglycans. […] Although the molecular mechanisms of silica-induced inflammation, fibrosis, and the related autoimmune responses have not been completely understood yet, there has been a generally accepted concept supporting the contribution of inflammation in the development of fibrosis and autoimmune responses due to silica inhalation.

• #2 Silicosis: New Challenges from an Old Inflammatory and Fibrotic Disease

  https://www.imrpress.com/journal/FBL/28/5/10.31083/j.fbl2805096/htm

  The mediators and cytokines that contribute to inflammation and pulmonary fibrosis are tumor necrosis factor alpha (TNF-α), TGF-β, interferon gamma (IFN-g), PDGF, proinflammatory interleukins (interleukin 1 beta [IL-1β], IL-2, IL-6, IL-8, IL-12), and fibronectin. […] The pathogenesis of silicosis may also be associated with an immunological mechanism, an idea supported by the identification of serum immunoglobulins, anti-DNA, and antinuclear factor antibodies in the serum of patients with silicosis.

• #2 Silicosis: New Challenges from an Old Inflammatory and Fibrotic Disease

  https://www.imrpress.com/journal/FBL/28/5/10.31083/j.fbl2805096/htm

  Most of the studies investigating the pathogenesis of silicosis have focused on the roles of alveolar macrophages and alveolar epithelial cells, which secrete pro-inflammatory and profibrotic mediators secondary to exposure to silica. […] Alveolar macrophages, alveolar epithelial cells, and fibroblasts are involved in the complex pathogenesis of silicosis. Alveolar macrophages are the first cells to react against inhaled silica particles, as they are found in the alveolar surfactant. […] The apoptosis of alveolar macrophages leads to pulmonary fibrosis. In addition, apoptotic alveolar macrophages release a significant amount of inflammatory factors, increasing inflammation. […] Silica particles can activate alveolar macrophages and also directly damage epithelial cells, which leads to the release of a large number of profibrotic factors (e.g., tumor transformation and growth factor beta [TGF-β], platelet-derived growth factor [PDGF]).

• #2 Silicosis

  https://www.iloencyclopaedia.org/part-i-47946/respiratory-system/item/418-silicosis

  Silicosis is a fibrotic disease of the lungs caused by the inhalation, retention and pulmonary reaction to crystalline silica. […] The precise pathogenesis of silicosis is uncertain, but an abundance of evidence implicates the interaction between the pulmonary alveolar macrophage and silica particles deposited in the lung. Surface properties of the silica particle appear to promote macrophage activation. These cells then release chemotactic factors and inflammatory mediators that result in a further cellular response by polymorphonuclear leukocytes, lymphocytes and additional macrophages. Fibroblast-stimulating factors are released that promote hyalinization and collagen deposition. The resulting pathologic silicotic lesion is the hyaline nodule, containing a central acellular zone with free silica surrounded by whorls of collagen and fibroblasts, and an active peripheral zone composed of macrophages, fibroblasts, plasma cells, and additional free silica as shown in figure 1.

• #2 Silicosis | Radiology Reference Article | Radiopaedia.org

  https://radiopaedia.org/articles/silicosis?lang=us

  Silicosis (plural: silicoses) is a fibrotic pneumoconiosis caused by the inhalation of fine particles of crystalline silicon dioxide (silica). Certain occupations such as mining, quarrying, denim sandblasting and tunneling are associated with silicosis. […] The disease occurs in two clinical forms that are subdivided by their temporal relationship to the exposure to silica: […] acute silicosis: manifests as alveolar silicoproteinosis […] classic silicosis: manifests as a chronic interstitial reticulonodular disease. […] The classic form is much more common than the acute form and can be classified as simple or complicated, according to the radiographic findings: […] simple silicosis: pattern of small and round or irregular opacities […] complicated silicosis: large conglomerate opacities that equate to progressive massive fibrosis.

• #2 BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis | Cell Death & Disease

  https://www.nature.com/articles/cddis201778

  A molecule known as TP53-upregulated modulator of apoptosis (BBC3/PUMA) is a member of the BCL2 family that contains a BCL2-like domain. […] Recent studies have demonstrated that BBC3 signaling mediates ROS production, DNA damage-dependent cell cycle arrest and caspase-independent apoptosis in macrophages through mitochondrial pathways, underscoring the potential role of BBC3 in the progression of some diseases caused by macrophage dysfunction. […] Some studies have shown the ability of BBC3 to induce autophagy through BAX activation and mitochondrial outer membrane permeabilization, which further enhanced apoptosis. […] In view of existing studies, we investigated the impact of BBC3 on macrophages differentiated from human leukemic U937 cells. […] We found that BBC3 induced macrophage autophagy and further led to cell activation and apoptosis in an in vitro model induced by SiO2.

• #2 BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis | Cell Death & Disease

  https://www.nature.com/articles/cddis201778

  These findings provide evidence that increased BBC3 expression and further enhancement of macrophage autophagy are involved in the development of silicosis, which improves the understanding of the link between BBC3 and silicosis. […] The results showed that the knockdown of Bbc3 with specific siRNA significantly decreased the expression of LC3BII and BECN1, but increased the expression of SQSTM1 compared with the scrambled siRNA control group. […] These results suggest that BBC3 regulated the activation and apoptosis of UDMs by activating autophagy.

• #2 The Mechanism and Effect of Autophagy, Apoptosis, and Pyroptosis on the Progression of Silicosis

  https://www.mdpi.com/1422-0067/22/15/8110

  Silicotic progression depends on the combined effect of silica and exogenous irritants, not silica alone. […] Pyroptosis may be a potential mechanism during the development of silicosis, and it should also be regarded as an “outcome variable” to assess the severity of pathological changes in silicosis.

• #2 Crystalline silica-induced recruitment and immuno-imbalance of CD4+ tissue resident memory T cells promote silicosis progression | Communications Biology

  https://www.nature.com/articles/s42003-024-06662-z

  Here we showed that a substantial accumulation of pulmonary CD4+ TRM cells mediated the pathogenesis of silicosis, which exerted immunological memory and antigen-specific response to the invaded CS particles. […] Targeting the immunosuppressive CD103+ TRM cells did not exert protective roles to silicosis. […] Neutralizing IL-7 in the lung disrupted the maintenance of TRM-Teff cells during silicosis progression and exerted protective effects.

• #2

  https://journals.lww.com/co-allergy/fulltext/2024/04000/association_between_silicosis_and_autoimmune.2.aspx

  There is a well established association between silica inhalational exposure and autoimmune disease, particularly in the context of intense exposure. […] Silica exposure is recognized as a causative factor for autoimmune disorders, with well established connections to conditions such as pulmonary fibrosis (silicosis), rheumatoid arthritis (Caplan’s syndrome), systemic sclerosis, systemic lupus erythematosus, and ANCA-related vasculitis/nephritis. […] Silica-stimulated macrophages trigger the activation of pattern recognition receptors (PRRs), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and the release of key mediators such as Interleukin 1-Beta (IL-1), Tumor Necrosis Factor alpha (TNF-), and interferons, playing a pivotal role in the pathogenesis of silicosis.

• #2 The Role of Fibrocyte in the Pathogenesis of Silicosis

  https://www.besjournal.com/article/doi/10.3967/bes2018.040

  Exposure to free silica induces silicosis and myofibroblasts are regarded as primary effector cells. Fibrocytes can differentiate into myofibroblast. Therefore, the present study was designed to investigate whether fibrocytes participate in silicosis. […] Results showed that fibrocytes participate in silicosis. […] Chronic inhalation of crystalline silica (SiO2) is associated with the development of silicosis, which is characterized by tissue remodelling, fibroproliferation, and deposition of extracellular matrix (ECM). […] Recent studies have demonstrated that epithelial-mesenchymal differentiation or recruitment of fibrocytes also contribute to myofibroblasts in lung fibrosis. […] Fibrocytes participate in both tissue fibrosis and tissue remodelling by producing ECM and matrix metalloproteinases.

• #2 The Role of Fibrocyte in the Pathogenesis of Silicosis

  https://www.besjournal.com/article/doi/10.3967/bes2018.040

  Our findings support the notion that fibrocytes may participate in silicosis and that different sources of myofibroblasts may play roles at different stages of silicosis. […] The results showed that fibrocyte-derived myofibroblasts (15%-35%) and AT-derived myofibroblasts (9%-21%) were increased in the lung tissue of silicosis rats at different time points. […] Fibrocytes are well-known to be capable of inflammatory chemotaxis and secreting chemokines, including inflammatory factors and chemokines, which not only maintain the local inflammatory microenvironment but also recruit many types of cells to amplify the inflammatory response. […] Our study suggests that fibrocytes may participate in silicosis and play an important role in the early stage of silicosis.

• #2 Anti‑fibrotic effects and the mechanism of action of miR‑29c in silicosis

  https://www.spandidos-publications.com/10.3892/mmr.2021.11932?text=fulltext

  The pathogenesis of silica dust-induced pulmonary fibrosis involves a complicated network of biological processes that include inflammation, immunological changes, cell cytotoxicity and tissue repair (5), as well as a variety of cell types and bioactive substances (1). […] The current RT-qPCR analysis also identified miR-29c downregulation in the lungs of silicotic rats, thereby validating our previous findings. […] These experiments therefore identified a potential mechanism via which miR-29c can contribute to the pathogenesis of silicosis. […] The present study concluded that miR-29c can inhibit the fibrotic process that underlies silicosis via its impact on TGF- signaling. […] The present study demonstrated that miR-29c expression was significantly decreased in in vivo and in vitro models of silicosis. It was identified that COL11, COL31, TGF-1 and -SMA, which are key fibrosis-related proteins, were regulated by miR-29c expression.

• #2 Distinct metabolic features in the plasma of patients with silicosis and dust-exposed workers in China: a case–control study | BMC Pulmonary Medicine | Full Text

  https://bmcpulmmed.biomedcentral.com/articles/10.1186/s12890-021-01462-1

  In the present study, the distinct metabolic features in the plasma of the patients of silicosis compared with that of DEWs were identified to be different. […] In the late pathogenesis of silicosis, the formation of silicotic nodules is the pathological manifestation of the production of collagen fibres and pulmonary interstitial fibrosis mediated by amino acid metabolism, which is consistent with the finding in the present study that arginine and proline metabolism was the major metabolic pathway in silicosis. […] Our data has shown that the plasma level of l-arginine in silicosis was significantly higher than that in the controls and was related to the decline of pulmonary function. […] The present study provided important information regarding sphingolipid metabolism and arginine and proline metabolism in DEWs and patients with silicosis, respectively.

• #2 Silicosis: New Challenges from an Old Inflammatory and Fibrotic Disease

  https://www.imrpress.com/journal/FBL/28/5/10.31083/j.fbl2805096/htm

  Inhalation of respirable silica particles leads to formation of mineral deposits in the terminal bronchioles and alveoli and induces pulmonary tissue reactions of the inflammatory type and proliferation of fibroblasts by complex pathogenic mechanisms, causing fibrosis as presented in Fig. 1. […] Disease severity and pathogenicity depend on the quantity of inhaled dust and the time of exposure. Under normal conditions, lung epithelial cells can replace damaged cells, due to exposure to silica dust through cell proliferation and differentiation. However, chronic exposure to silica dust can lead to repetitive damage and repair of airway epithelia, resulting in depletion of airway epithelial stem cells in pulmonary silicosis. […] Lung tissue reactions result from the joint action of several mechanisms, such as the direct cytotoxic effects of silica particles on macrophages, activation of the surface of receptors of the macrophages, rupture of lysosomes, production of free radicals, activation of inflammasomes, production of cytokines and growth factors, and cellular apoptosis, which finally lead to fibrosis.

• #2 Treatment Drugs for Silicosis | Encyclopedia MDPI

  https://encyclopedia.pub/entry/45514

  Extensive research has revealed that the development of silicosis fibrosis is not solely due to one factor, but rather a complex outcome resulting from various factors and links. The primary pathogenic mechanisms of silicosis involve direct cytotoxic effects, the generation of ROS and reactive nitrogen radicals, the release of inflammatory chemokines, the initiation of fibrotic pathways and cell death. […] Silicosis and IPF are respiratory diseases that cause damage to the lungs. In response to the inflammatory process, fibroblasts proliferate and produce excessive collagen fibers, leading to the deposition of ECM lung tissue remodeling, ultimately resulting in impaired lung function. Moreover, the two diseases share similarities in the upregulation of TGF-β and extracellular signal-regulated kinase (ERK) signaling pathways in cytokine and growth factor pathways, and a relationship with autophagy. While the immediate causes of silicosis and IPF may differ, the overall mechanisms of the subsequent profibrotic reaction are comparable, being characterized by ECM deposition and fibroblast proliferation. Therefore, potential therapeutic drugs for the treatment of silicosis may be sought from IPF.

• #3 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8072896/

  Silica particles are recognized by receptors localized on the surface of alveolar macrophages. Among all classes of scavenger receptors (SR), transmembrane proteins SR-AI, SR-AII and macrophage receptors with a collagenous structure (MARCO) are most associated with silica binding. […] Respirable silica particles (10 m), which pass through a mucociliary defence mechanism, may reach distal lung compartments where they initiate a cascade of actions, leading to the development of lung silicosis. In the terminal airways and alveoli, the inhaled silica is engulfed by alveolar macrophages, which are primarily responsible for clearing the lung from debris. However, silica is extremely toxic for macrophages. […] The cytotoxicity of silica particles may be explained by several hypotheses. Crystalline silica (quartz, cristoballite, and some forms of tridymite) are inherently piezoelectric, i.e., they generate opposite electric charges on opposite sides of the physical structure during the application of pressure. These piezoelectric properties of the crystals, particularly of those freshly fractured, trigger the generation of ROS.

• #3 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8072896/

  There are several sources of ROS and reactive nitrogen species (RNS) associated with interaction of silica with macrophages. […] Besides direct cytotoxicity, free radicals act as important initiators of a wide cascade of cellular responses, including mitogen-activated protein kinase (MAPK) phosphorylation, activation of transcription factors nuclear factor (NF)-B and activator protein (AP)-1, and activation of inflammasome. […] After recognition of silica by alveolar macrophages, they engulf the silica particles. The internalized silica is entrapped by lysosomes, where a low pH-activated variety of enzymes is prepared to digest the particle. However, the silica particle cannot be broken down by the enzymes, which results in the loss of lysosomal membrane integrity and the release of lysosomal enzymes, including protease cathepsin B.

• #3

  https://journals.lww.com/co-allergy/fulltext/2024/04000/association_between_silicosis_and_autoimmune.2.aspx

  There is a well established association between silica inhalational exposure and autoimmune disease, particularly in the context of intense exposure. […] Silica exposure is recognized as a causative factor for autoimmune disorders, with well established connections to conditions such as pulmonary fibrosis (silicosis), rheumatoid arthritis (Caplan’s syndrome), systemic sclerosis, systemic lupus erythematosus, and ANCA-related vasculitis/nephritis. […] Silica-stimulated macrophages trigger the activation of pattern recognition receptors (PRRs), NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3) inflammasome, and the release of key mediators such as Interleukin 1-Beta (IL-1), Tumor Necrosis Factor alpha (TNF-), and interferons, playing a pivotal role in the pathogenesis of silicosis.

• #3 Silicosis pathophysiology – wikidoc

  https://www.wikidoc.org/index.php/Silicosis_pathophysiology

  The toxicity of crystalline silica results from the ability of crystalline silica surfaces to interact with aqueous media, to generate oxygen radicals, and to injure target pulmonary cells such as alveolar macrophages. Generation of inflammatory cytokines (eg, interleukin-1 and tumor necrosis factor beta) by target cells results in cytokine networking between inflammatory cells and resident pulmonary cells, which in turn leads to inflammation and fibrosis. […] The alveolar macrophages are implicated as the major cell type in fibrogenesis, but other immune cells, namely neutrophils, T-lymphocytes, and mast cells are also involved. […] Injury to the alveolar type I epithelial cell is regarded as an early event in fibrogenesis followed by hyperplasia and hypertrophy of type II epithelial cells.

• #3 Silicosis: biomarkers and pathogenesis – MedCrave online

  https://medcraveonline.com/JLPRR/silicosis-biomarkers-and-pathogenesis.html

  Respirable silica particles with 3-1 microns in diameter are directly deposited in the pulmonary alveoli and interact with pulmonary alveolar macrophages causing the silicosis disease. The nature and extent of the lung response depend on the intensity of inspired silica particles. Silica particles that deposit in the pulmonary alveoli promote pulmonary alveolar macrophage activation by releasing several chemotactic factors and inflammatory mediators. These factors and mediators cause releasing of the fibroblast stimulating factor via the cellular response of the lymphocytes and leukocytes. Fibroblast-stimulating factor promote collagen deposition and hyalinization in the pulmonary tissues resulting in pulmonary nodule that composes of a central acellular zone with containing free silica. Crystalline silica-laden macrophages cause cell death, fibrous proliferation, and finally pulmonary fibrosis. Pulmonary fibrosis is progressively magnified by re-ingestion of silica particles by macrophages. However, pathogenesis of silicosis may due to abnormal immunological mechanism.

• #4 New Insights into Pathomechanisms and Treatment Possibilities for Lung Silicosis

  https://www.mdpi.com/1422-0067/22/8/4162

  The initial toxicity to macrophages and silica-induced production of ROS seem to be the critical mechanisms of initiation and progression of inflammation and fibrosis. […] After recognition of silica by alveolar macrophages, they engulf the silica particles. The internalized silica is entrapped by lysosomes, where a low pH-activated variety of enzymes is prepared to digest the particle. However, the silica particle cannot be broken down by the enzymes, which results in the loss of lysosomal membrane integrity and the release of lysosomal enzymes, including protease cathepsin B. […] Silica-induced activation of inflammasome is a fundamental pathway leading to lung injury. […] In silica-induced lung inflammation and injury, NLRP3 inflammasome is of fundamental importance. […] The presence of any pathogen-associated molecular patterns (PAMPs) or danger-associated molecular patterns (DAMPs) removes this auto-regression, and NLRP3 inflammasome is activated.

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