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A schematic of the experimental design and effects of apoptotic cell instillation with or without simvastatin on efferocytic ability of alveolar macrophages in bleomycin-stimulated lungs. (a) Arrows indicate the time point of treatment with bleomycin (BLM), apoptotic Jurkat T cells (ApoJ), or simvastatin. (b, c) Apoptotic Jurkat cells were once instillated on day 2 or twice on days 2 and 7 after bleomycin treatment. Simvastatin (Simv; 20 mg/kg/d, i.p) or its vehicle (Veh; 2% DMSO in saline) was administered with or without second apoptotic cell instillation and every day thereafter. Mice were killed on days 7 (2 h after second apoptotic cell or simvastatin treatment) and 14 following BLM treatment. (b) Phagocytic indices were measured in BAL alveolar macrophages. (c) Representative photomicrographs from five mice per group showing cytospin-stained BAL cells on day 7 after BLM treatment. Arrowheads indicate alveolar macrophages with engulfed apoptotic cells or fragments. Scale bar = 50 μM. Values represent the mean ± S.E.M. of results from five mice per group. *Po0.05 compared with saline control, + Po0.05 as indicated, # Po0.05 for BLM+twice Apo (Apo (2))+Simv versus BLM+single Apo (Apo (1)), § Po0.05 for BLM+Apo (2)+Simv versus BLM+Apo (2)
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A single early-phase infusion of apoptotic cells can inhibit bleomycin-induced lung inflammation and fibrosis; however, it is unknown whether these effects can be enhanced with additional infusions and/or statin treatment. Here, we investigated whether an increased frequency of apoptotic cell injection, with or without efferocytosis enhancer simvas...
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Context 1
... Thus, we examined whether an increased frequency of apoptotic cell injection with or without simvas- tatin enhances efferocytic ability of alveolar macrophages in a bleomycin-induced murine fibrosis model. The schematic drawing of experimental design was presented in the Figure 1a. We observed that an additional apoptotic cell infusion, or simvastatin treatment alone (BLM+twice Apo and BLM+single Apo+Simv, respectively) 7 days post-bleomycin treatment did not enhance phagocytic indices in alveolar macrophages 2 h after infusion, when compared to a single early apoptotic cell infusion (BLM+single Apo; Figures 1b and c). ...
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... these indices significantly increased after an additional apoptotic cell infusion combined with simvastatin (BLM+twice Apo+Simv). Similarly, on day 14 post-bleomycin treatment, efferocytic ability of alveolar macrophages was further enhanced in the BLM+twice Apo+Simv group, compared to the BLM+Apo (single or twice) or the BLM +single Apo+Simv groups (Figure 1b). ...
Context 3
... co-administration of the second apoptotic cell infusion with simvastatin further enhanced PPARγ mRNA expression in alveolar macrophages and lung tissue and activity in lung tissue, compared with the BLM +Apo (single or twice) or the BLM+single Apo+Simv groups. Similarly, mRNA and/or protein abundances of PPARγ targets, such as CD36 and macrophage mannose receptor (MMR), were enhanced in alveolar macrophages (Figures 3a and c) and lung tissue (Figures 3b and d; Supplementary Figure 1a and b) from the BLM+twice Apo+Simv group on days 7 and 14 post-bleomycin treatment. No significant changes in expression were observed in the BLM+single Apo, BLM+twice Apo, and BLM+single Apo+Simv groups. ...
Context 4
... represent the mean ± S.E.M. of results from five mice per group. *Po0.05 compared with saline control, + Po0.05 as indicated, # Po0.05 for BLM+twice Apo (Apo (2))+Simv versus BLM+single Apo (Apo (1)), § Po0.05 for BLM+Apo (2)+Simv versus BLM+Apo (2) alveolar macrophages in the milieu with endogenously- generated apoptotic cells. In addition, further studies are needed to determine the alternative mechanisms, including oxidative stress, protease/anti-protease imbalance, or increase the inhibitory macrophage receptor signal regulatory protein-alpha (SIRPα), which all play important roles in the regulation of apoptotic cell clearance, 30,31 in bleomycin- induced fibrosis, using simvastatin, PPARγ agonists/antago- nists, or RhoA inhibitors. ...
Citations
... All procedures involving mice were guided by the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Using mouse pharyngeal instillation, BLM (5 U/kg body weight in 30 μl sterile saline) in a test solution was delivered (Lee et al. 2017;Yoon et al. 2013). One day prior to BLM treatment, rGas6 (50 µg/kg) was injected intraperitoneally (i.p.) and then every two days following that (Peng et al. 2019;Kim et al. 2021). ...
... Bronchoalveolar lavage (BAL), cell counts, and lung tissue BAL was conducted according to previously described methods (Lee et al. 2017;Yoon et al. 2013). After BAL samples were centrifuged at 500 × g for 5 min at 4 °C, cell pellets were cleaned and reconstituted in phosphate-buffered medium. ...
... Using previously published techniques, primary ATII cells were extracted from mice (Bortnick et al. 2003;Lee et al. 2017). In summary, the lungs were perfused with a solution of 0.9% saline by injecting it into the pulmonary artery until the blood was extracted. ...
The epithelial-mesenchymal transition (EMT) and fibroblast activation are major events in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 administration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fibroblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast activation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.
... Mice were cared for and handled in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals. Mouse pharyngeal aspiration was used to administer a test solution containing BLM (5 U/kg body weight in 30 µl sterile saline (0.9% sodium chloride)) [24,25]. rGas6 (50 µg/kg) or saline treatment was given intraperitoneally (i.p.) 1 day before BLM treatment and then once every 2 days thereafter [20,21]. ...
... Primary murine ATII cells were isolated from mice as previously described [24]. In brief, the lungs were perfused with 0.9% saline injected through the pulmonary artery until the blood was cleared. ...
... The final cell isolates were seeded on type I collagen-coated 35-mm dishes in Ham's F12 culture medium supplemented with 15 mM HEPES, 0.8 mM CaCl2, 0.25% bovine serum albumin, 5 mg/ml insulin, 5 mg/ml transferrin, 5 ng/ml sodium selenite, and 2% mouse serum. Isolated type II cells were reported to be approximately 90% pure, as assessed using cytokeratin staining and Nile red-positive vacuoles with pro-SP-C immunofluorescence staining [24,29]. ...
The epithelial-mesenchymal transition (EMT) is a major event in idiopathic pulmonary fibrosis pathogenesis. Here, we investigated whether growth arrest-specific protein 6 (Gas6) plays a protective role in lung fibrosis via suppression of the EMT and fibroblast activation. rGas6 ad-ministration inhibited the EMT in isolated mouse ATII cells 14 days post-BLM treatment based on morphologic cellular alterations, changes in mRNA and protein expression profiles of EMT markers, and induction of EMT-activating transcription factors. BLM-induced increases in gene expression of fibroblast activation-related markers and the invasive capacity of primary lung fi-broblasts in primary lung fibroblasts were reversed by rGas6 administration. Furthermore, the hydroxyproline content and collagen accumulation in interstitial areas with damaged alveolar structures in lung tissue were reduced by rGas6 administration. Targeting Gas6/Axl signaling events with specific inhibitors of Axl (BGB324), COX-2 (NS-398), EP1/EP2 receptor (AH-6809), or PGD2 DP2 receptor (BAY-u3405) reversed the inhibitory effects of rGas6 on EMT and fibroblast activation. Finally, we confirmed the antifibrotic effects of Gas6 using Gas6−/− mice. Therefore, Gas6/Axl signaling events play a potential role in inhibition of EMT process and fibroblast acti-vation via COX-2-derived PGE2 and PGD2 production, ultimately preventing the development of pulmonary fibrosis.
... Some of the mechanisms by which statins cause anti-inflammatory effects include, 1) suppressing the innate immune response by preventing neutrophil migration, oxidative stress, activation of nuclear factor kappa B (NF-κB), release of pro-inflammatory mediators, the expression of matrix metalloproteinases (MMPs), and the expression of bleomycininduced epithelial-mesenchymal transition (EMT) markers, 2) increasing the expression of constitutive nitric oxide (NO) synthase, extracellular signal-regulated kinase 5 (ERK5), peroxisome proliferator-activated receptors (PPARs) [e.g., PPARα, PPARδ, PPARγ, as well as PPARγmediated cluster of differentiation 36 (CD36)], and 3) increasing the expression of interleukin (IL)-10, hepatocyte growth factor (HGF), and A. Tajbakhsh, S.M. Gheibihayat, H. Askari et al. Pharmacology & Therapeutics 238 (2022) 108282 transforming growth factor-beta (TGF-β1) (Baccante et al., 2004;Bahrami, Parsamanesh, Atkin, Banach, & Sahebkar, 2018;Bellosta et al., 1998;Fessler et al., 2005a;Furman et al., 2004;Heo et al., 2014;Khalifeh, Penson, Banach, & Sahebkar, 2021;Laufs & Liao, 1998;Lee et al., 2017a;Martin et al., 2001;Pahan, Sheikh, Namboodiri, & Singh, 1997;Rikitake et al., 2001;Rosenson, Tangney, & Casey, 1999;Zelvyte, Dominaitiene, Crisby, & Janciauskiene, 2002). In the mevalonate pathway, statins decrease mevalonate release and reduce inflammation through the phosphatidylinositol 3'-kinase (PI3K)-Akt, ERK, and MAPK pathways (Fig. 2). ...
... It is known that a single early-phase infusion of ACs may be beneficial in an experimental mouse model of bleomycininduced lung inflammation and fibrosis. Lee et al. used this model to determine whether therapeutic benefits achieved with an infusion of ACs could be augmented with an additional infusion of ACs and/or a statin [simvastatin (20 mg/kg/d)] treatment (n.b., simvastatin enhances efferocytosis and PPARγ activity) (Lee et al., 2017a). Their results demonstrated that an additional administration of ACs with simvastatin further enhanced the efferocytic capacity of alveolar macrophages and increased the expression of PPARγ-dependent CD36, as well as mannose receptor (MMR) macrophages (Lee et al., 2017a). ...
... Lee et al. used this model to determine whether therapeutic benefits achieved with an infusion of ACs could be augmented with an additional infusion of ACs and/or a statin [simvastatin (20 mg/kg/d)] treatment (n.b., simvastatin enhances efferocytosis and PPARγ activity) (Lee et al., 2017a). Their results demonstrated that an additional administration of ACs with simvastatin further enhanced the efferocytic capacity of alveolar macrophages and increased the expression of PPARγ-dependent CD36, as well as mannose receptor (MMR) macrophages (Lee et al., 2017a). The anti-EMT and anti-fibrotic effects (i.e., two major events in the pathogenesis of idiopathic pulmonary fibrosis) induced by early AC infusion are enhanced by simvastatin (Lee et al., 2017a;Wolters, Collard, & Jones, 2014). ...
Efferocytosis (clearance of apoptotic cells by phagocytosis without inducing inflammation and autoimmunity) is an important mechanism in the resolution of inflammatory processes. Efficient efferocytosis inhibits the accumulation of apoptotic cells/debris and maintains homeostasis before the onset of necrosis (secondary necrosis), which promotes inflammation or injury. Moreover, the detection and clearance of apoptotic cells can promote anti-inflammatory responses. Defective efferocytosis is involved in the pathogenesis of several diseases, such as atherosclerosis, chronic inflammation, autoimmunity and cancer. Statins are 3-hydroxy-3-methylglutaryl coenzyme A-reductase inhibitors which exert cholesterol-lowering effects plus multiple pleiotropic properties, such as inhibition of inflammation and macrophage proliferation. Statins exhibit anti-inflammatory properties by reducing both the prenylation of signaling molecules with downregulation of gene expression and the expression of adhesion molecules, as well as the levels of cytokines and chemokines. Additionally, statins suppress the prenylation of GTPases, such as Rac-1, as a positive regulator of efferocytosis, and RhoA, as a negative regulator of efferocytosis. However, statins alter the membrane balance of Rho GTPases in efferocytosis toward Rac-1. Efferocytosis has modifiable targets, which can be exploited for the treatment of several diseases, although limited attention has been given to the mechanisms by which statins regulate efferocytosis and the resulting therapeutic implications. In this review, we will elaborate on the mechanisms underlying the modulation of apoptotic cell clearance by statins, which, in turn, inhibits uncontrolled inflammation and ensuing diseases.
... Mast cell granules contain histamine and TGF-β; following degranulation, the components can promote the proliferation of fibroblasts, and alveolar macrophages can also secrete TGF-β, thereby promoting the enhancement of collagen fiber synthesis and leading to the deposition of ECM [100]. In 2017, Lee et al. found that simvastatin was able to promote the antifibrotic properties associated with the early perfusion of apoptotic cells in the middle stage of bleomycin-induced pulmonary fibrosis in mice, and the combined action of simvastatin and the administration of apoptotic cells further enhanced the expression of PPAR-γ in alveolar macrophages and inhibited the pulmonary fibrotic response [101]. The beneficial effects of simvastatin on IPF are primarily achieved by enhancing the specific anti-EMT and antifibrotic properties of AECIIs and lung fibroblasts. ...
Idiopathic pulmonary fibrosis (IPF) is a type of interstitial lung disease (ILD) characterized by the proliferation of fibroblasts and aberrant accumulation of extracellular matrix. These changes are accompanied by structural destruction of the lung tissue and the progressive decline of pulmonary function. In the past few decades, researchers have investigated the pathogenesis of IPF and sought a therapeutic approach for its treatment. Some studies have shown that the occurrence of IPF is related to pulmonary inflammatory injury; however, its specific etiology and pathogenesis remain unknown, and no effective treatment, with the exception of lung transplantation, has been identified yet. Several basic science and clinical studies in recent years have shown that statins, the traditional lipid-lowering drugs, exert significant antifibrotic effects, which can delay the progression of IPF and impairment of pulmonary function. This article is aimed at summarizing the current understanding of the pathogenesis of IPF, the progress of research on the use of statins in IPF models and clinical trials, and its main molecular targets.
... An increasing body of evidence has indicated that statins may have a beneficial effect on clinical outcomes in PF and even in COVID-19. 23,[36][37][38] By searching all the literature investigating the association of statins with PF, including 7 clinical studies 23,24,39-43 and 18 experimental studies, 24,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] we found that almost all studies trends to indicate that the statins are protective for PF (Supporting information Table S3). It is believed that lipophilic statins are taken up faster by PF lung tissue through passive diffusion than through active uptake. ...
... An increasing body of evidence has indicated that statins may have a beneficial effect on clinical outcomes in PF and even in COVID-19. 23,[36][37][38] By searching all the literature investigating the association of statins with PF, including 7 clinical studies 23,24,39-43 and 18 experimental studies, 24,36,[44][45][46][47][48][49][50][51][52][53][54][55][56][57][58][59] we found that almost all studies trends to indicate that the statins are protective for PF (Supporting information Table S3). It is believed that lipophilic statins are taken up faster by PF lung tissue through passive diffusion than through active uptake. ...
Treatments for pulmonary fibrosis (PF) are ineffective because its molecular pathogenesis and therapeutic targets are unclear. Here, we show that the expression of low-density lipoprotein receptor (LDLR) was significantly decreased in alveolar type II (ATII) and fibroblast cells, whereas it was increased in endothelial cells from systemic sclerosis-related PF (SSc-PF) patients and idiopathic PF (IPF) patients compared with healthy controls. However, the plasma levels of low-density lipoprotein (LDL) increased in SSc-PF and IPF patients. The disrupted LDL-LDLR metabolism was also observed in four mouse PF models. Upon bleomycin (BLM) treatment, Ldlr-deficient (Ldlr-/-) mice exhibited remarkably higher LDL levels, abundant apoptosis, increased fibroblast-like endothelial and ATII cells and significantly earlier and more severe fibrotic response compared to wild-type mice. In vitro experiments revealed that apoptosis and TGF-β1 production were induced by LDL, while fibroblast-like cell accumulation and ET-1 expression were induced by LDLR knockdown. Treatment of fibroblasts with LDL or culture medium derived from LDL-pretreated endothelial or epithelial cells led to obvious fibrotic responses in vitro. Similar results were observed after LDLR knockdown operation. These results suggest that disturbed LDL-LDLR metabolism contributes in various ways to the malfunction of endothelial and epithelial cells, and fibroblasts during pulmonary fibrogenesis. In addition, pharmacological restoration of LDLR levels by using a combination of atorvastatin and alirocumab inhibited BLM-induced LDL elevation, apoptosis, fibroblast-like cell accumulation and mitigated PF in mice. Therefore, LDL-LDLR may serve as an important mediator in PF, and LDLR enhancing strategies may have beneficial effects on PF.
... Antioxidant supplementation improved macrophage functions and mitigated hyperoxia-induced lung injury [32]. In addition, resolvins [33,34], statins, and pioglitazone have been shown to enhance macrophage-mediated apoptotic cell clearance [35][36][37]. The present study revealed that hyperoxia dampens macrophagemediated efferocytosis, and Nrf2 deficiency worsens it. ...
Recognition and clearance of apoptotic cells by phagocytes (also known as efferocytosis), primarily mediated by macrophages, are essential to terminate lung inflammatory responses and promote tissue repair after injury. The Nrf2 transcription factor is crucial for cytoprotection and host defense. Previously, we showed sustained neutrophilic lung inflammation in Nrf2-deficient (Nrf2−/−) mice after hyperoxia-induced lung injury in vivo, but the mechanisms underlying this abnormal phenotype remain unclear. To examine whether Nrf2 regulates apoptotic neutrophil clearance, we used the alveolar macrophages (AMФs) and bone-marrow-derived macrophages (BMDMФs) of wild-type (WT) and Nrf2−/− mice. We found that the efferocytic ability of AMФ was impaired in hyperoxia-exposed mice’s lungs, but the effect was more pronounced in Nrf2−/− mice. Importantly, AMФ-mediated efferocytosis remained impaired in Nrf2−/− mice recovering from injury but was restored to the basal state in the wild-type counterparts. Hyperoxia affected apoptotic neutrophil binding, not internalization, in both WT and Nrf2−/− BMDMФs, but the effect was more significant in the latter cells. Augmenting Nrf2 activity restored hyperoxia attenuated efferocytosis in WT, but not in Nrf2−/− macrophages. However, the loss of Nrf2 in neutrophils affected their uptake by WT macrophages. Collectively, these results demonstrate that Nrf2 is required for optimal macrophage-mediated efferocytosis and that activating Nrf2 may provide a physiological way to accelerate apoptotic cell clearance after oxidant injury.
... Some of the mechanisms by which statins cause anti-inflammatory effects include, 1) suppressing the innate immune response by preventing neutrophil migration, oxidative stress, activation of nuclear factor kappa B (NF-κB), release of pro-inflammatory mediators, the expression of matrix metalloproteinases (MMPs), and the expression of bleomycininduced epithelial-mesenchymal transition (EMT) markers, 2) increasing the expression of constitutive nitric oxide (NO) synthase, extracellular signal-regulated kinase 5 (ERK5), peroxisome proliferator-activated receptors (PPARs) [e.g., PPARα, PPARδ, PPARγ, as well as PPARγmediated cluster of differentiation 36 (CD36)], and 3) increasing the expression of interleukin (IL)-10, hepatocyte growth factor (HGF), and A. Tajbakhsh, S.M. Gheibihayat, H. Askari et al. Pharmacology & Therapeutics 238 (2022) 108282 transforming growth factor-beta (TGF-β1) (Baccante et al., 2004;Bahrami, Parsamanesh, Atkin, Banach, & Sahebkar, 2018;Bellosta et al., 1998;Fessler et al., 2005a;Furman et al., 2004;Heo et al., 2014;Khalifeh, Penson, Banach, & Sahebkar, 2021;Laufs & Liao, 1998;Lee et al., 2017a;Martin et al., 2001;Pahan, Sheikh, Namboodiri, & Singh, 1997;Rikitake et al., 2001;Rosenson, Tangney, & Casey, 1999;Zelvyte, Dominaitiene, Crisby, & Janciauskiene, 2002). In the mevalonate pathway, statins decrease mevalonate release and reduce inflammation through the phosphatidylinositol 3'-kinase (PI3K)-Akt, ERK, and MAPK pathways (Fig. 2). ...
... It is known that a single early-phase infusion of ACs may be beneficial in an experimental mouse model of bleomycininduced lung inflammation and fibrosis. Lee et al. used this model to determine whether therapeutic benefits achieved with an infusion of ACs could be augmented with an additional infusion of ACs and/or a statin [simvastatin (20 mg/kg/d)] treatment (n.b., simvastatin enhances efferocytosis and PPARγ activity) (Lee et al., 2017a). Their results demonstrated that an additional administration of ACs with simvastatin further enhanced the efferocytic capacity of alveolar macrophages and increased the expression of PPARγ-dependent CD36, as well as mannose receptor (MMR) macrophages (Lee et al., 2017a). ...
... Lee et al. used this model to determine whether therapeutic benefits achieved with an infusion of ACs could be augmented with an additional infusion of ACs and/or a statin [simvastatin (20 mg/kg/d)] treatment (n.b., simvastatin enhances efferocytosis and PPARγ activity) (Lee et al., 2017a). Their results demonstrated that an additional administration of ACs with simvastatin further enhanced the efferocytic capacity of alveolar macrophages and increased the expression of PPARγ-dependent CD36, as well as mannose receptor (MMR) macrophages (Lee et al., 2017a). The anti-EMT and anti-fibrotic effects (i.e., two major events in the pathogenesis of idiopathic pulmonary fibrosis) induced by early AC infusion are enhanced by simvastatin (Lee et al., 2017a;Wolters, Collard, & Jones, 2014). ...
... Introduction Atherosclerosis is associated with system inflammation markers of interstitial lung disease (ILD) and pulmonary fibrosis (ILD-PF), including interleukin (IL)-6, IL-17, and the antiinflammatory IL-10, as well as angiotensin-converting enzyme 2 (ACE2) [1][2][3][4][5][6]. Therefore, ILD-PF is considered an immunomodulatory and system inflammatory disease. ...
Purpose
To determine the effects of statins and steroids on the risk of coronary artery disease (CAD) and stroke in patients with interstitial lung disease and pulmonary fibrosis (ILD-PF).
Methods
We retrospectively enrolled patients with ILD-PF who were using statins (statin cohort, N = 11,567) and not using statins (nonstatin cohort, N = 26,159). Cox proportional regression was performed to analyze the cumulative incidence of CAD and stroke. Adjusted hazard ratios (aHRs) and 95% confidence intervals (CIs) of CAD and stroke were determined after sex, age, and comorbidities, as well as the use of inhaler corticosteroids (ICSs), oral steroids (OSs), and statins, were controlled for.
Results
Compared with those of patients without statin use, the aHRs (95% CIs) of patients with statin use for CAD and ischemic stroke were 0.72 (0.65–0.79) and 0.52 (0.38–0.72), respectively. For patients taking single-use statins but not ICSs/OSs, the aHRs (95% CIs) for CAD and ischemic stroke were 0.72 (0.65–0.79)/0.69 (0.61–0.79) and 0.54 (0.39–0.74)/0.50 (0.32–0.79), respectively. For patients using ICSs/OSs, the aHRs (95% CIs) for CAD and ischemic stroke were 0.71 (0.42–1.18)/0.74 (0.64–0.85) and 0.23 (0.03–1.59)/0.54 (0.35–0.85), respectively.
Conclusions
The findings demonstrate that statin use, either alone or in combination with OS use, plays an auxiliary role in the management of CAD and ischemic stroke in patients with ILD-PF.
... Intratracheal infusion of apoptotic thymocytes in the context of HDM exposure had the effect of suppressing Th2 cytokine expression and reducing airway eosinophilia, thought to be mediated by induction of the suppressor of cytokine signaling molecule SOCS3 and adenosine receptors in alveolar macrophages (175). The administration of apoptotic macrophages has also been investigated as a means of inhibiting bleomycin-induced lung inflammation and fibrosis, with the intriguing finding that the additional delivery of simvastatin along with apoptotic macrophages further enhanced efferocytosis in alveolar macrophages and moreover increased PPARg activity, induced hepatocyte growth factor and interleukin-10 expression, and decreased the expression of factors associated with epithelial to mesenchymal transition (176). Additionally, a study by Woo et al. recently revealed a critical role for GM-CSF signaling in alveolar macrophages in the regulation of allergic inflammation (177). ...
Macrophages are dynamic cells that play critical roles in the induction and resolution of sterile inflammation. In this review, we will compile and interpret recent findings on the plasticity of macrophages and how these cells contribute to the development of non-infectious inflammatory diseases, with a particular focus on allergic and autoimmune disorders. The critical roles of macrophages in the resolution of inflammation will then be examined, emphasizing the ability of macrophages to clear apoptotic immune cells. Rheumatoid arthritis (RA) is a chronic autoimmune-driven spectrum of diseases where persistent inflammation results in synovial hyperplasia and excessive immune cell accumulation, leading to remodeling and reduced function in affected joints. Macrophages are central to the pathophysiology of RA, driving episodic cycles of chronic inflammation and tissue destruction. RA patients have increased numbers of active M1 polarized pro-inflammatory macrophages and few or inactive M2 type cells. This imbalance in macrophage homeostasis is a main contributor to pro-inflammatory mediators in RA, resulting in continual activation of immune and stromal populations and accelerated tissue remodeling. Modulation of macrophage phenotype and function remains a key therapeutic goal for the treatment of this disease. Intriguingly, therapeutic intervention with glucocorticoids or other DMARDs promotes the re-polarization of M1 macrophages to an anti-inflammatory M2 phenotype; this reprogramming is dependent on metabolic changes to promote phenotypic switching. Allergic asthma is associated with Th2-polarised airway inflammation, structural remodeling of the large airways, and airway hyperresponsiveness. Macrophage polarization has a profound impact on asthma pathogenesis, as the response to allergen exposure is regulated by an intricate interplay between local immune factors including cytokines, chemokines and danger signals from neighboring cells. In the Th2-polarized environment characteristic of allergic asthma, high levels of IL-4 produced by locally infiltrating innate lymphoid cells and helper T cells promote the acquisition of an alternatively activated M2a phenotype in macrophages, with myriad effects on the local immune response and airway structure. Targeting regulators of macrophage plasticity is currently being pursued in the treatment of allergic asthma and other allergic diseases. Macrophages promote the re-balancing of pro-inflammatory responses towards pro-resolution responses and are thus central to the success of an inflammatory response. It has long been established that apoptosis supports monocyte and macrophage recruitment to sites of inflammation, facilitating subsequent corpse clearance. This drives resolution responses and mediates a phenotypic switch in the polarity of macrophages. However, the role of apoptotic cell-derived extracellular vesicles (ACdEV) in the recruitment and control of macrophage phenotype has received remarkably little attention. ACdEV are powerful mediators of intercellular communication, carrying a wealth of lipid and protein mediators that may modulate macrophage phenotype, including a cargo of active immune-modulating enzymes. The impact of such interactions may result in repair or disease in different contexts. In this review, we will discuss the origin, characterization, and activity of macrophages in sterile inflammatory diseases and the underlying mechanisms of macrophage polarization via ACdEV and apoptotic cell clearance, in order to provide new insights into therapeutic strategies that could exploit the capabilities of these agile and responsive cells.
... By limiting the synthesis of this moiety, RhoA cannot be prenylated, thereby preventing this negative regulator of efferocytosis from being recruited to the plasma membrane [251,254,255]. As a result, Rac-1 can mediate efferocytic cup formation and apoptotic cell engulfment unopposed by RhoA activity [252,256]. Simvastatin, for example, was observed to inhibit RhoA in murine lungs infused with apoptotic cells, with simvastatin reducing the fibrosis and damage that otherwise follows infusion of apoptotic cells into the airways [256]. Notably, the effects of simvastatin were also shown in alveolar macrophages from human patients with COPD [201]. ...
... As a result, Rac-1 can mediate efferocytic cup formation and apoptotic cell engulfment unopposed by RhoA activity [252,256]. Simvastatin, for example, was observed to inhibit RhoA in murine lungs infused with apoptotic cells, with simvastatin reducing the fibrosis and damage that otherwise follows infusion of apoptotic cells into the airways [256]. Notably, the effects of simvastatin were also shown in alveolar macrophages from human patients with COPD [201]. ...
Pneumonia and inflammatory diseases of the pulmonary system such as chronic obstructive pulmonary disease and asthma continue to cause significant morbidity and mortality globally. While the etiology of these diseases is highly different, they share a number of similarities in the underlying inflammatory processes driving disease pathology. Multiple recent studies have identified failures in efferocytosis—the phagocytic clearance of apoptotic cells—as a common driver of inflammation and tissue destruction in these diseases. Effective efferocytosis has been shown to be important for resolving inflammatory diseases of the lung and the subsequent restoration of normal lung function, while many pneumonia-causing pathogens manipulate the efferocytic system to enhance their growth and avoid immunity. Moreover, some treatments used to manage these patients, such as inhaled corticosteroids for chronic obstructive pulmonary disease and the prevalent use of statins for cardiovascular disease, have been found to beneficially alter efferocytic activity in these patients. In this review, we provide an overview of the efferocytic process and its role in the pathophysiology and resolution of pneumonia and other inflammatory diseases of the lungs, and discuss the utility of existing and emerging therapies for modulating efferocytosis as potential treatments for these diseases.
