Mouse Model Of Silicosis Research Articles

Engineering Macrophage-Derived Exosome to Deliver Pirfenidone: A Novel Approach to Combat Silicotic Pulmonary Fibrosis.

Silicosis is a severe lung disease characterized by diffuse pulmonary fibrosis, for which there is currently no effective treatment. Pirfenidone (PFD) shows great antifibrotic potential but is clinically hindered by low bioavailability and gastrointestinal side effects. To address these limitations, this study develops a PFD delivery system (PFD-Exo) using J774A.1 macrophage-derived exosomes. Firstly, PFD is loaded via sonication, then PFD-Exo is characterized using Raman spectral imaging and UV absorption spectroscopy. Finally, in vitro and in vivo silicosis models are established to evaluate its antifibrotic effects. Results show that PFD-Exo outperforms free PFD in inhibiting TGF-β1-induced transdifferentiation of primary lung fibroblasts in vitro. In a mouse model of silicosis, PFD-Exo is found to be accumulated in the lungs following intratracheal administration and significantly ameliorates pulmonary inflammation and fibrosis while minimizing gastrointestinal side effects. Mechanistic studies reveal that PFD-Exo modulates the TGF-β signaling pathway by downregulating SMAD3 and upregulating SMAD7 and NOGGIN. In conclusion, this study provides the first evidence of macrophage-derived exosomes as an effective PFD delivery system for silicosis treatment and offers a promising strategy for other refractory pulmonary diseases.

Jun and JunB members of the AP-1 complex are potential therapeutic targets for silicosis

Silicosis is a systemic disease with predominantly diffuse fibrosis of the lungs due to prolonged inhalation of free SiO2 dust during the manufacturing process, for which there is no effective treatment. In this study, we used a combined epigenetic and transcriptomic approach to reveal the chromatin-opening features of silicosis and identify the key transcription factor activator protein 1 (AP-1) that responds to silicosis fibrosis. Therapeutic administration of an AP-1 inhibitor inhibits the PI3K/AKT signaling pathway, reduces fibrosis marker proteins, and significantly ameliorates lung fibrosis in a mouse model of silicosis. In addition, it was observed that the expression of Jun and JunB was significantly up-regulated in a TGF-β1-induced in vitro transdifferentiation model of NIH/3T3 cells, and Co-IP confirmed that a protein complex could be formed between Jun and JunB. Mechanistically, silencing of Jun and JunB expression reversed the activation of the PI3K/AKT signaling pathway and the upregulation of fibrosis marker proteins in NIH/3 T3 cells after TGF-β1 stimulation. Taken together, Jun/JunB is expected to be a potential therapeutic target for silicosis fibrosis.

Trigonelline hydrochloride attenuates silica-induced pulmonary fibrosis by orchestrating fibroblast to myofibroblast differentiation

BackgroundSilicosis represents a paramount occupational health hazard globally, with its incidence, morbidity, and mortality on an upward trajectory, posing substantial clinical dilemmas due to limited effective treatment options available. Trigonelline (Trig), a plant alkaloid extracted mainly from coffee and fenugreek, have diverse biological properties such as protecting dermal fibroblasts against ultraviolet radiation and has the potential to inhibit collagen synthesis. However, it’s unclear whether Trig inhibits fibroblast activation to attenuate silicosis-induced pulmonary fibrosis is unclear.MethodsTo evaluate the therapeutic efficacy of Trig in the context of silicosis-related pulmonary fibrosis, a mouse model of silicosis was utilized. The investigation seeks to elucidated Trig's impact on the progression of silica-induced pulmonary fibrosis by evaluating protein expression, mRNA levels and employing Hematoxylin and Eosin (H&E), Masson's trichrome, and Sirius Red staining. Subsequently, we explored the mechanism underlying of its functions.ResultsIn vivo experiment, Trig has been demonstrated the significant efficacy in mitigating SiO2-induced silicosis and BLM-induced pulmonary fibrosis, as evidenced by improved histochemical staining and reduced fibrotic marker expressions. Additionally, we showed that the differentiation of fibroblast to myofibroblast was imped in Trig + SiO2 group. In terms of mechanism, we obtained in vitro evidence that Trig inhibited fibroblast-to-myofibroblast differentiation by repressing TGF-β/Smad signaling according to the in vitro evidence. Notably, our finding indicated that Trig seemed to be safe in mice and fibroblasts.ConclusionIn summary, Trig attenuated the severity of silicosis-related pulmonary fibrosis by alleviating the differentiation of myofibroblasts, indicating the development of novel therapeutic approaches for silicosis fibrosis.

Inhibition of macrophage pyroptosis ameliorates silica-induced pulmonary fibrosis

Macrophage pyroptosis has recently been involved in some inflammatory and fibrosis diseases, however, the role of macrophage pyroptosis in silica-induced pulmonary fibrosis has not been fully elucidated. In this study, we explored the role of macrophage pyroptosis in silicosis in vivo and in vitro. A mouse model of silicosis was established and mice were sacrificed at 7, 14, and 28 days after exposure of silica. The results revealed that the expression of GSDMD and other pyroptosis-related indicators was up-regulated obviously at 14 days after silica exposure, indicating that silica induced pyroptosis in vivo. In vitro, human monocytic leukemia cells (THP-1) and human lung fibroblasts (MRC-5) were used to detect the relationship between macrophage pyroptosis and lung fibroblasts. It showed that silica increased the levels of GSDMD and other pyroptosis-related indicators remarkably in macrophages and the supernatant of macrophage stimulated by silica could promote the upregulation of fibrosis markers in fibroblasts. However, GSDMD knockdown suppressed silica-induced macrophage pyroptosis and alleviated the upregulation of fibrosis markers in fibroblasts, suggesting the important role of macrophage pyroptosis in the activation of myofibroblasts during the progression of silicosis. Taken together, it showed that silica could induce macrophage pyroptosis and inhibiting macrophage pyroptosis could be a feasible clinical strategy to alleviate silicosis.

Macrophage-derived MMP12 promotes fibrosis through sustained damage to endothelial cells

Macrophages are essential for the maintenance of endothelial cell function. However, the potential impact and mechanisms of crosstalk between macrophages and endothelial cells during silicosis progression remain unexplored. To fill this knowledge gap, a mouse model of silicosis was established. Single cell sequencing, spatial transcriptome sequencing, western blotting, immunofluorescence staining, tube-forming and wound healing assays were used to explore the effects of silicon dioxide on macrophage-endothelial interactions. To investigate the mechanism of macrophage-mediated fibrosis, MMP12 was specifically inactivated using siRNA and pharmacological approaches, and macrophages were depleted using disodium chlorophosphite liposomes. Compared to the normal saline group, the silica dust group showed altered macrophage-endothelial interactions. Matrix metalloproteinase family member MMP12 was identified as a key mediator of the altered function of macrophage-endothelial interactions after silica exposure, which was accompanied by pro-inflammatory macrophage activation and fibrotic progression. By using ablation strategies, macrophage-derived MMP12 was shown to mediate endothelial cell dysfunction by accumulating on the extracellular matrix. During the inflammatory phase of silicosis, MMP12 secreted by pro-inflammatory macrophages caused decreased endothelial cell viability, reduced migration, decreased trans-endothelial resistance and increased permeability; while during the fibrotic phase, macrophage-derived MMP12 sustained endothelial cell injury through accumulation on the extracellular matrix.

Development of nintedanib nanosuspension for inhaled treatment of experimental silicosis.

Silicosis is an irreversible and progressive fibrotic lung disease caused by massive inhalation of crystalline silica dust at workplaces, affecting millions of industrial workers worldwide. A tyrosine kinase inhibitor, nintedanib (NTB), has emerged as a potential silicosis treatment due to its inhibitory effects on key signaling pathways that promote silica-induced pulmonary fibrosis. However, chronic and frequent use of the oral NTB formulation clinically approved for treating other fibrotic lung diseases often results in significant side effects. To this end, we engineered a nanocrystal-based suspension formulation of NTB (NTB-NS) possessing specific physicochemical properties to enhance drug retention in the lung for localized treatment of silicosis via inhalation. Our NTB-NS formulation was prepared using a wet-milling procedure in presence of Pluronic F127 to endow the formulation with nonadhesive surface coatings to minimize interactions with therapy-inactivating delivery barriers in the lung. We found that NTB-NS, following intratracheal administration, provided robust anti-fibrotic effects and mechanical lung function recovery in a mouse model of silicosis, whereas a 100-fold greater oral NTB dose given with a triple dosing frequency failed to do so. Importantly, several key pathological phenotypes were fully normalized by NTB-NS without displaying notable local or systemic adverse effects. Overall, NTB-NS may open a new avenue for localized treatment of silicosis and potentially other fibrotic lung diseases.

Lysophosphatidylcholine acyltransferase 1 alleviates silica-induced pulmonary fibrosis by modulating lipid metabolism

Silicosis is an incurable lung disease that can progress even when exposure to silica dust has ended. Lipid metabolism plays an important role in the occurrence and development of silicosis. However, the mechanistic details have not been fully elucidated. This was investigated in the current study by high-performance liquid chromatography-mass spectrometry-based lipidomic analysis of lung tissue in a mouse model of silicosis. Lipid profiles and key metabolic enzymes were compared between silica and control groups. The lipidomic analysis revealed differentially-expressed lipids in the lungs of silicosis mice compared with controls. Among the identified lipid metabolism-related enzymes, the expression of lysophosphatidylcholine acyltransferase 1 (LPCAT1) was significantly down-regulated at the transcript and protein levels. LPCAT1 overexpression in vivo using adeno-associated virus altered the balance between phosphatidylcholine and lysophosphatidylcholine and inhibited the development of silicosis in mice. These results indicate that LPCAT1 dysregulation leads to abnormal lipid metabolism and silicosis, and is a potential therapeutic target for the treatment of silica-induced pulmonary fibrosis.

Differential on N6-methyladenosine modification of circRNA in early inflammation of silicosis

Objective: To explore the difference of methylation of circRNA related m6A in early inflammation of silicosis and to elucidate the underlying molecular mechanism of circRNA involved in the process of silicosis. Methods: The activation markers of macrophages were detected by Western blotting (WB) in THP-1-derived macrophages. The cell viability was detected with CCK8, by which the stimulation concentration and time of silica were determined. The methylation of total RNA was determined by colorimetry, and the expression of RNA m6A methylase, demethylase and reading protein were detected by Western blotting in mouse model of silicosis. The differential expression of m6A modified circRNA in lung tissues form silicosis and control mice was obtained through Arraystar m6A circRNA epigenetic transcriptome Chip and verified by RT-PCR. Results: The concentration of SiO(2) at 50 μg/cm(2) had the most significant effect on the activation markers and activity of macrophages. Compared with the control group, SiO(2) increased the total RNA m6A level of macrophages, and there were significant differences in the expression of methylase METTL3 and reading protein YTDHF3. High throughput sequencing analysis showed that compared with the control group, the methylation levels of 132 circRNA m6A in the lung of silicosis model mice were increased, while the methylation levels of 296 circRNA m6A were decreased, and then the target circSLC2A13 was screened based on the basic expression. Further verification showed that SiO(2) significantly increased the expression of circSLC2A13 and m6A modification in macrophages. Conclusion: The methylation of circRNA m6A is involved in the activation of macrophages in early inflammation of silicosis.

Necroptosis in pulmonary macrophages promotes silica-induced inflammation and interstitial fibrosis in mice

Silicosis is a disease characterized by extensive lung nodules and fibrosis caused by the prolonged inhalation of silica in occupational settings. However, the molecular mechanism of silicosis development is complex and not fully understood. Furthermore, the role of necroptosis, a death receptor-mediated and caspase-independent mode of inflammatory cell death, is not well understood in silicosis. Here, we demonstrate that the necroptotic signaling pathway of macrophages is significantly activated in the lungs of silicosis mouse models. Meanwhile, increased M1 macrophage infiltration and up-regulation of pro-inflammatory cytokines (TNF-α, IL-6) were observed in our silicosis model. Notably, the expression of the pro-fibrotic factor, TGF-β1, and fibrosis biomarkers α-SMA and collagen I were also unregulated; however, these phenomena were recovered by Nec-1, an inhibitor specific for RIP1 kinase-dependent necroptosis. We conclude that macrophage-mediated necroptosis promotes the progression of silicosis by enhancing lung inflammatory responses and fibrogenesis in a mouse model of silicosis. These findings provide new insights for drug discovery and clinical treatment of silicosis.

Lipopolysaccharides promote pulmonary fibrosis in silicosis through the aggravation of apoptosis and inflammation in alveolar macrophages.

Alveolar macrophages (AMs) play an important defensive role by removing dust and bacteria from alveoli. Apoptosis of AMs is associated with lung fibrosis; however, the relationship between this apoptotic event and environmental factors, such as the presence of lipopolysaccharides (LPSs) in the workplace, has not yet been addressed. To investigate whether exposure to LPS can exacerbate fibrosis, we collected AMs from 12 male workers exposed to silica and incubated them in the presence and absence of LPS for 24 h. We show that the levels of cleaved caspase-3 and pro-inflammatory cytokines interleukin (IL)-1β, IL-6, and tumor necrosis factor-alpha were increased in these AMs following LPS treatment. Moreover, we demonstrate that LPS exposure aggravated apoptosis and the release of inflammatory factors in AMs in a mouse model of silicosis, which eventually promoted pulmonary fibrosis. These results suggest that exposure to LPS may accelerate the progression of pulmonary fibrosis in silicosis by increasing apoptosis and inflammation in AMs.

Efferocytosis mediated by TAM receptors maintains lung homeostasis and controls inflammation in a mouse model of silicosis

Abstract Alveolar macrophages (AMs) are key cells for the establishment of pulmonary homeostasis. Efferocytosis is one of the main regulatory mechanisms for maintaining tolerance and homeostasis. The TAM receptor family (Tyro3, Axl and MerTk) mediates efferocytosis and inhibits proinflammatory pathways through Gas6 or Protein S binding to phosphatidylserine on apoptotic cells. Here we investigated how lung macrophages are regulated by TAM receptors in homeostasis and during silicosis. We found that LPS-stimulated AMs have an impaired ability to secrete IL-1b, IL-6, IFN-b, and MCP-1, but produce high levels of TNF-a and lower levels of IL-10, compared to bone marrow derived macrophages (BMDM). During homeostasis, AMs from wild type (WT) mice showed high expression of Axl, MerTk, and Gas6 by RT-PCR. Compared to WT mice, Axl−/− and MerTk−/− mice had more airway cells, less TGF-b and IL-10, and higher levels of IL-17 and KC within BAL. In addition, both KO mice had a higher frequency and number of AMs in the BAL, and secreted high levels of MCP-1, IFN-b, GM-CSF, and IL-10 following LPS stimulation compared to WT mice. Fifteen days after intra-tracheal silica instillation (SiO2; 20 mg), Axl−/− and MerTk−/− mice lost more body weight, and had increased lung weight, and percentage and number of neutrophils in the BAL compared to WT mice. Furthermore, both KO mice had a decreased percentage of AMs, and higher levels of KC, TNF-α and TGF-β but lower levels of IL-10 in the BAL compared to WT mice. Finally, Axl−/− mice had higher levels of IL-1β and IL-6 in the BAL than MerTk−/− mice. Our data suggest that efferocytosis mediated by Axl and MerTk receptors plays an important role in maintaining homeostasis and controlling inflammation in the pulmonary mucosae.

N-acetylcysteine tiherapeutically protects against pulmonary fibrosis in a mouse model of silicosis.

Silicosis is a lethal pneumoconiosis disease characterized by chronic lung inflammation and fibrosis. The present study was to explore the effect of against crystalline silica (CS)-induced pulmonary fibrosis. A total of 138 wild-type C57BL/6J mice were divided into control and experimental groups, and killed on month 0, 1, 2, 3, 4, and 5. Different doses of N-acetylcysteine (NAC) were gavaged to the mice after CS instillation to observe the effect of NAC on CS induced pulmonary fibrosis and inflammation. The pulmonary injury was evaluated with Hematoxylin and eosin/Masson staining. Reactive oxygen species level was analyzed by DCFH-DA labeling. Commercial ELISA kits were used to determine antioxidant activity (T-AOC, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) and cytokines (TNF-α, IL-1β, IL-4, and IL-6). The expression of oxidising enzymes (NOX2, iNOS, SOD2, and XO) were detected by real time PCR. Immunohistochemistry (IHC) staining was performed to examine epithelial-mesenchymal transition-related markers. The mice treated with NAC presented markedly reduced CS-induced pulmonary injury and ameliorated CS-induced pulmonary fibrosis and inflammation. The level of malondialdehyde was reduced, while the activities of GSH-PX, SOD, and T-AOC were markedly enhanced by NAC. We also found the down-regulation of oxidising enzymes (NOX2, iNOS, SOD2, and XO) after NAC treatment. Moreover, E-cadherin expression was increased while vimentin and Cytochrome C expressions were decreased by NAC. These encouraging findings suggest that NAC exerts pulmonary protective effects in CS-induced pulmonary fibrosis and might be considered as a promising agent for the treatment of silicosis.

MiR-1224-5p Mediates Mitochondrial Damage to Affect Silica-Induced Pulmonary Fibrosis by Targeting BECN1.

Silicosis is associated with fibroblast proliferation and extracellular matrix deposition in lung tissues. The dysregulation of miR-1224-5p has been implicated in several human cancers; however, the expression and function of miR-1224-5p in silicosis is unknown. The mitochondrial dysfunctions play critical roles in some diseases, but how these processes are regulated in silicosis remains limited. Here, we explored the role of miR-1224-5p in a mouse model of silicosis. We showed that the expression of miR-1224-5p is increased both in lung tissues of silica-induced pulmonary fibrosis and fibroblasts exposed to TGF-β1. Repression of miR-1224-5p expression attenuated silica-induced fibrotic progression in vivo and TGF-β1-induced myofibroblast differentiation in vitro. Additionally, we demonstrated that miR-1224-5p facilitated silica-induced pulmonary fibrosis primarily by repressing one of target genes, BECN1, thereby blocking PARK2 translocation to mitochondria and inducing the accumulation of damaged mitochondria. Furthermore, the activation of PDGFR signal mediated by mitochondrial damage and insufficient mitophagy resulted in myofibroblast differentiation. Collectively, these data indicated that miR-1224-5p exerts key functions in silica-induced pulmonary fibrosis and may represent a potential therapeutic target for silicosis.

Muc1 deficiency exacerbates pulmonary fibrosis in a mouse model of silicosis

BackgroundMUC1 (MUC in human and Muc in animals) is a membrane-tethered mucin expressed on the apical surface of lung epithelial cells. However, in the lungs of patients with interstitial lung disease, MUC1 is aberrantly expressed in hyperplastic alveolar type II epithelial (ATII) cells and alveolar macrophages (AM), and elevated levels of extracellular MUC1 are found in bronchoalveolar lavage (BAL) fluid and the serum of these patients. While pro-fibrotic effects of extracellular MUC1 have recently been described in cultured fibroblasts, the contribution of MUC1 to the pathobiology of pulmonary fibrosis is unknown. In this study, we hypothesized that MUC1 deficiency would reduce susceptibility to pulmonary fibrosis in a mouse model of silicosis. MethodsWe employed human MUC1 transgenic mice, Muc1 deficient mice and wild-type mice on C57BL/6 background in these studies. Some mice received a one-time dose of crystalline silica instilled into their oropharynx in order to induce pulmonary fibrosis and assess the effects of Muc1 deficiency on fibrotic and inflammatory responses in the lung. ResultsAs previously described in other mouse models of pulmonary fibrosis, we found that extracellular MUC1 levels were markedly increased in whole lung tissues, BALF and serum of human MUC1 transgenic mice after silica. We also detected an increase in total MUC1 levels in the lungs of these mice, indicating that production as well as release contributed to elevated levels after lung injury. Immunohistochemical staining revealed that increased MUC1 expression was mostly confined to ATII cells and AMs in areas of fibrotic remodeling, illustrating a pattern similar to the expression of MUC1 in human fibrotic lung tissues. However, contrary to our hypothesis, we found that Muc1 deficiency resulted in a worsening of fibrotic remodeling in the mouse lung as judged by an increase in number of silicotic nodules, an increase in lung collagen deposition and an increase in the severity of pulmonary inflammation. ConclusionsAltogether, our results indicate that Muc1 has anti-fibrotic properties in the mouse lung and suggest that elevated levels of MUC1 in patients with interstitial lung disease may serve a protective role, which aims to limit the severity of tissue remodeling in the lung.

BBC3 in macrophages promoted pulmonary fibrosis development through inducing autophagy during silicosis

Following inhalation into the lungs, silica particles are engulfed by alveolar macrophages, which triggers endogenous or exogenous apoptosis signaling pathways. As an inducer of apoptosis, the role of BBC3/PUMA (BCL2-binding component 3) in macrophages during silicosis remains unknown. Here, we exposed U937 cell-derived macrophages (UDMs) to SiO2in vitro to explore the function of BBC3 in SiO2-induced disease. 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. In addition, 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. The conditioned medium from macrophages exposed to SiO2 promoted the proliferation and migration of fibroblasts, and the inhibition of BBC3/autophagy reduced the effects of the conditioned medium on fibroblasts. In the mouse model of silicosis, Bbc3 knockout mice clearly exhibited decreased levels of autophagy and fibrosis progression. These results suggest that downregulation of BBC3 expression may become a novel therapeutic strategy for the treatment of silicosis.

MiR-489 inhibits silica-induced pulmonary fibrosis by targeting MyD88 and Smad3 and is negatively regulated by lncRNA CHRF.

Silicosis is an incurable occupational disease associated with inflammation, fibroblast proliferation and the accumulation of extracellular matrix in lung tissues. The dysregulation of lncRNAs and miRNAs has been implicated in many complex diseases; however, the current understanding of their roles in fibrotic lung diseases, especially silicosis, remains limited. Our previous microRNA (miRNA, miR) microarray data have indicated decreased expression levels of miR-489 in lung tissues of silica-induced pulmonary fibrosis. Here, we further explored the role of miR-489 in a mouse model of silicosis. Interestingly, miR-489 levels were reduced in both macrophages that were exposed to silica and fibroblasts that were exposed to TGF-β1. Additionally, the overexpressed miR-489 carried out its anti-fibrotic role by attenuating inflammation and fibrotic progression in vivo. Our molecular study further demonstrated that miR-489 inhibited silica-induced pulmonary fibrosis primarily by repressing its target genes MyD88 and Smad3. Moreover, the up-regulated lncRNA cardiac hypertrophy-related factor (CHRF) reversed the inhibitory effect of miR-489 on MyD88 and Smad3 and then triggered the inflammation and fibrotic signaling pathways. Overall, our data indicate that the CHRF-miR-489-MyD88 Smad3 signaling axis exerts key functions in silica-induced pulmonary fibrosis and may represent a therapeutic target for silicosis.

Th17 can regulate silica-induced lung inflammation through an IL-1β-dependent mechanism.

Silicosis is an occupational lung disease caused by the inhalation of silica dust and characterized by lung inflammation and fibrosis. Interleukin (IL)-1β is induced by silica and functions as the key pro-inflammatory cytokine in this process. The Th17 response, which is induced by IL-1β, has been reported very important in chronic human lung inflammatory diseases. To elucidate the underlying mechanisms of IL-1β and IL-17 in silicosis, we used anakinra and an anti-IL-17 monoclonal antibody (mAb) to block the receptor of IL-1β (IL-RI) and IL-17, respectively, in a mouse model of silicosis. We observed increased IL-1β expression and an enhanced Th17 response after silica instillation. Treatment with an IL-1 type I receptor (IL-1RI) antagonist anakinra substantially decreased silica-induced lung inflammation and the Th17 response. Lung inflammation and the accumulation of inflammatory cells were attenuated in the IL-17-neutralized silicosis group. IL-17 may promote lung inflammation by modulating the differentiation of Th1 and regulatory T cells (Tregs) and by regulating the production of IL-22 and IL-1β during the lung inflammation of silicosis. Silica may induce IL-1β production from alveolar macrophages and promote inflammation by initiating a Th17 response via an IL-1β/IL-1RI-dependent mechanism. The Th17 response could induce lung inflammation during the pathogenesis of silicosis by regulating the homoeostasis of the Th immune responses and affecting the production of IL-22 and IL-1β. This study describes a potentially important inflammatory mechanism of silicosis that may bring about novel therapies for this inflammatory and fibrotic disease.

The role of complement in experimental silicosis

The role of the complement system in the pathogenesis of crystal-induced pulmonary inflammation and fibrosis was evaluated using a mouse model of silicosis and congenitally complement-deficient mice. Mice lacking the fifth component of complement (B10.D2/o) were compared to C5-sufficient animals (B10.D2/n) for pulmonary changes following intratracheal instillation of silica crystals. Complement-deficient mice demonstrated a significant reduction compared to complement-sufficient mice in both cell number and protein content of lung lavage fluid throughout the 12 weeks following silica exposure. Lung hydroxyproline content (indicative of collagen deposition) was equivalent for both strains and significantly higher than controls at all time points following silica instillation. Moreover, studies in vitro have shown that silica crystals are capable of activating complement via the alternative pathway. These studies indicate that the complement system may be responsible for some of the pulmonary inflammation, but not fibrosis elicited by silica exposure.