Journal Of Inflammation (London, England)[JOURNAL]
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200 papers
Progranulin (PGRN) as a regulator of inflammation and a critical factor in the immunopathogenesis of cardiovascular diseases.
Saeedi-Boroujeni A, Purrahman D, Shojaeian A … +3 more , Poniatowski ŁA, Rafiee F, Mahmoudian-Sani MR
J Inflamm (Lond) · 2023 Jan · PMID 36658641 · Full text
Immune dysregulation has been identified as a critical cause of the most common types of cardiovascular diseases (CVDs). Notably, the innate and adaptive immune responses under physiological conditions are typically regu...
Immune dysregulation has been identified as a critical cause of the most common types of cardiovascular diseases (CVDs). Notably, the innate and adaptive immune responses under physiological conditions are typically regulated with high sensitivity to avoid the exacerbation of inflammation, but any dysregulation can probably be associated with CVDs. In this respect, progranulin (PGRN) serves as one of the main components of the regulation of inflammatory processes, which significantly contributes to the immunopathogenesis of such disorders. PGRN has been introduced among the secreted growth factors as one related to wound healing, inflammation, and human embryonic development, as well as a wide variety of autoimmune diseases. The relationship between the serum PGRN and TNF-α ratio with the spontaneous bacterial peritonitis constitute one of the independent predictors of these conditions. The full-length PGRN can thus effectively reduce the calcification of valve interstitial cells, and the granulin precursor (GRN), among the degradation products of PGRN, can be beneficial. Moreover, it was observed that, PGRN protects the heart against ischemia-reperfusion injury. Above all, PGRN also provides protection in the initial phase following myocardial ischemia-reperfusion injury. The protective impact of PGRN on this may be associated with the early activation of the PI3K/Akt signaling pathway. PGRN also acts as a protective factor in hyperhomocysteinemia, probably by down-regulating the wingless-related integration site Wnt/β-catenin signaling pathway. Many studies have further demonstrated that SARS-CoV-2 (COVID-19) has dramatically increased the risks of CVDs due to inflammation, so PGRN has drawn much more attention among scholars. Lysosomes play a pivotal role in the inflammation process, and PGRN is one of the key regulators in their functioning, which contributes to the immunomodulatory mechanism in the pathogenesis of CVDs. Therefore, investigation of PGRN actions can help find new prospects in the treatment of CVDs. This review aims to summarize the role of PGRN in the immunopathogenesis of CVD, with an emphasis on its treatment.
Neutrophil extracellular traps and pulmonary fibrosis: an update.
Yan S, Li M, Liu B … +2 more , Ma Z, Yang Q
J Inflamm (Lond) · 2023 Jan · PMID 36658568 · Full text
Pulmonary fibrosis (PF) is a serious and often fatal illness that occurs in various clinical settings and represents a significant unmet medical need. Increasing evidence indicates that neutrophil extracellular traps (NE...
Pulmonary fibrosis (PF) is a serious and often fatal illness that occurs in various clinical settings and represents a significant unmet medical need. Increasing evidence indicates that neutrophil extracellular traps (NETs) contribute significantly to the progression of PF. Therefore, understanding the pathways by which NETs contribute to the disease is crucial for developing effective treatments. This review focuses on the formation of NETs and the common mechanisms of NETs in PF.
Bystander effect of SARS-CoV-2 spike protein on human monocytic THP-1 cell activation and initiation of prothrombogenic stimulus representing severe COVID-19.
Patra T, Ray R
J Inflamm (Lond) · 2022 Dec · PMID 36585712 · Full text
BACKGROUND: Hypercoagulable state and thromboembolic complications are potential life-threatening events in COVID-19 patients. Our previous studies demonstrated that SARS-CoV-2 infection as well as viral spike protein ex...
BACKGROUND: Hypercoagulable state and thromboembolic complications are potential life-threatening events in COVID-19 patients. Our previous studies demonstrated that SARS-CoV-2 infection as well as viral spike protein expressed epithelial cells exhibit senescence with the release of inflammatory molecules, including alarmins. FINDINGS: We observed extracellular alarmins present in the culture media of SARS-CoV-2 spike expressing cells activate human THP-1 monocytes to secrete pro-inflammatory cytokines to a significant level. The release of THP-1 derived pro-inflammatory cytokine signature correlated with the serum of acute COVID-19 patient, but not in post-COVID-19 state. Our study suggested that the alarmins secreted by spike expressing cells, initiated phagocytosis property of THP-1 cells. The phagocytic monocytes secreted complement component C5a and generated an autocrine signal via C5aR1 receptor. The C5a-C5aR1 signal induced formation of monocyte mediated extracellular trap resulted in the generation of a prothrombogenic stimulus with activating platelets and increased tissue factor activity. We also observed an enhanced C5a level, platelet activating factor, and high tissue factor activity in the serum of acute COVID-19 patients, but not in recovered patients. CONCLUSION: Our present study demonstrated that SARS-CoV-2 spike protein modulates monocyte responses in a paracrine manner for prothrombogenic stimulus by the generation of C5a complement component.
Efficacy of probiotic Streptococcus thermophilus in counteracting TGF-β1-induced fibrotic response in normal human dermal fibroblasts.
Lombardi F, Augello FR, Artone S … +6 more , Bahiti B, Sheldon JM, Giuliani M, Cifone MG, Palumbo P, Cinque B
J Inflamm (Lond) · 2022 Dec · PMID 36536411 · Full text
BACKGROUND: Abnormal and deregulated skin wound healing associated with prolonged inflammation may result in dermal fibrosis. Since the current therapeutic strategies revealed unsatisfactory, the investigation of alterna...
BACKGROUND: Abnormal and deregulated skin wound healing associated with prolonged inflammation may result in dermal fibrosis. Since the current therapeutic strategies revealed unsatisfactory, the investigation of alternative approaches such as those based on the use of specific probiotic strains could provide promising therapeutic options. In this study, we aimed to evaluate whether the lysate from S. thermophilus could antagonize the fibrogenic effects of TGF-β1 in normal human dermal fibroblasts (NHDF). METHODS: NHDF were exposed to TGF-β1 to establish a fibrotic phenotype. Proliferation rate and cell number were measured using the IncuCyte® Live Cell Imager system and the trypan blue dye exclusion test. Phenoconversion markers (α-SMA and fibronectin) and collagen I levels were assessed by western blot and immunofluorescence. The mRNA levels of TGF-β1 were evaluated by RT-PCR. The Smad2/3 phosphorylation level as well as β-catenin and PPARγ expression, were assessed by western blot. The cell contractility function and migration of NHDF were studied using collagen gel retraction assay, and scratch wound healing assay, respectively. The effects of S. thermophilus lysate, alone or combined with TGF-β1, were evaluated on all of the above-listed parameters and markers associated with TGF-β1-induced fibrotic phenotype. RESULTS: Exposure to the S. thermophilus lysate significantly reduced the key mediators and events involved in the abnormal activation of myofibroblasts by TGF-β1 within the fibrotic profile. The S. thermophilus treatment significantly reduced cell proliferation, migration, and myo-differentiation. In addition, the treatment with probiotic lysate reduced the α-SMA, fibronectin, collagen-I expression levels, and affected the collagen contraction ability of activated dermal fibroblasts. Moreover, the probiotic targeted the TGF-β1 signaling, reducing Smad2/3 activation, TGF-β1 mRNA level, and β-catenin expression through the upregulation of PPARγ. CONCLUSION: This is the first report showing that S. thermophilus lysate had a remarkable anti-fibrotic effect in TGF-β1-activated NHDF by inhibiting Smad signaling. Notably, the probiotic was able to reduce β-catenin and increase PPARγ levels. The findings support our point that S. thermophilus may help prevent or treat hypertrophic scarring and keloids.
Combination of IL-17A/F and TNF-α uniquely alters the bronchial epithelial cell proteome to enhance proteins that augment neutrophil migration.
Altieri A, Piyadasa H, Hemshekhar M … +6 more , Osawa N, Recksiedler B, Spicer V, Hiemstra PS, Halayko AJ, Mookherjee N
J Inflamm (Lond) · 2022 Dec · PMID 36517803 · Full text
BACKGROUND: The heterodimer interleukin (IL)-17A/F is elevated in the lungs in chronic respiratory disease such as severe asthma, along with the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Although IL-17A/...
BACKGROUND: The heterodimer interleukin (IL)-17A/F is elevated in the lungs in chronic respiratory disease such as severe asthma, along with the pro-inflammatory cytokine tumor necrosis factor-α (TNF-α). Although IL-17A/F and TNF-α are known to functionally cooperate to exacerbate airway inflammation, proteins altered by their interaction in the lungs are not fully elucidated. RESULTS: We used Slow Off-rate Modified Aptamer-based proteomic array to identify proteins that are uniquely and/or synergistically enhanced by concurrent stimulation with IL-17A/F and TNF-α in human bronchial epithelial cells (HBEC). The abundance of 38 proteins was significantly enhanced by the combination of IL-17A/F and TNF-α, compared to either cytokine alone. Four out of seven proteins that were increased > 2-fold were those that promote neutrophil migration; host defence peptides (HDP; Lipocalin-2 (LCN-2) and Elafin) and chemokines (IL-8, GROα). We independently confirmed the synergistic increase of these four proteins by western blots and ELISA. We also functionally confirmed that factors secreted by HBEC stimulated with the combination of IL-17A/F and TNF-α uniquely enhances neutrophil migration. We further showed that PI3K and PKC pathways selectively control IL-17A/F + TNF-α-mediated synergistic production of HDPs LCN-2 and Elafin, but not chemokines IL-8 and GROα. Using a murine model of airway inflammation, we demonstrated enhancement of IL-17A/F, TNF-α, LCN-2 and neutrophil chemokine KC in the lungs, thus corroborating our findings in-vivo. CONCLUSION: This study identifies proteins and signaling mediated by concurrent IL-17A/F and TNF-α exposure in the lungs, relevant to respiratory diseases characterized by chronic inflammation, especially neutrophilic airway inflammation such as severe asthma.
Evaluation of asthma-chronic obstructive pulmonary disease overlap using a mouse model of pulmonary disease.
Jo YS, Rhee CK, Yoon HK … +4 more , Park CK, Lim JU, An TJ, Hur J
J Inflamm (Lond) · 2022 Dec · PMID 36474247 · Full text
BACKGROUND: Features of asthma and chronic obstructive pulmonary disease (COPD) can coexist in the same patient, in a condition termed asthma- chronic obstructive pulmonary disease overlap (ACO). ACO is heterogeneous con...
BACKGROUND: Features of asthma and chronic obstructive pulmonary disease (COPD) can coexist in the same patient, in a condition termed asthma- chronic obstructive pulmonary disease overlap (ACO). ACO is heterogeneous condition exhibiting various combinations of asthma and COPD features. No clinically acceptable experimental model of ACO has been established. We aimed to establish an animal model of ACO. METHODS: We generated two phenotypes of ACO by administering ovalbumin and porcine pancreatic elastase in combination, and papain. The proinflammatory cytokines and cell types in bronchoalveolar lavage fluid (BALF) were investigated, and lung function parameters were measured using the FlexiVent system. RESULTS: Greater airway inflammation was observed in the asthma and both ACO models, and emphysema was found in the COPD and both ACO models. The proportion of eosinophils in BALF was elevated in the asthma and ACO-a model. Type 2 inflammatory cytokine levels were highest in the ACO-a model, and the neutrophil gelatinase-associated lipocalin level was elevated in the asthma and ACO-a model. Of lung function parameters, compliance was greater in the COPD and ACO-b model, in which elastance was lower than in the asthma model. Airway resistance increased with the methacholine concentration in the asthma and both ACO models, but not in the control or COPD model. CONCLUSION: We established two murine models of ACO that exhibit features of asthma and COPD. We validated the clinical relevance of the ACO models based on changes in cytokine profiles and lung function. These models will be useful in further studies of the pathogenesis of, and therapeutic targets for ACO.
The immunological function of CXCR2 in the liver during sepsis.
Liu N, Bauer M, Press AT
J Inflamm (Lond) · 2022 Nov · PMID 36451225 · Full text
BACKGROUND: The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mi...
BACKGROUND: The chemokine receptor CXCR2 and its ligands, especially CXCL8, are crucial mediators for the progression of liver inflammation and liver failure in sepsis. Neutrophils have the highest CXCR2 expression in mice and humans, and their activation via CXCL8 facilitates their migration to the inflamed liver for the clearance of the pathogens and, in turn, the inflammation. MAIN BODY: In sepsis, the inflammatory insult causes extensive neutrophil migration to the liver that overwhelms the immune response. To compensate for the strong receptor activation, CXCR2 desensitizes, incapacitating the immune cells to efficiently clear pathogens, causing further life-threatening liver damage and uncontrolled pathogen spread. CONCLUSION: CXCR2 function during infection strongly depends on the expressing cell type. It signals pro- and anti-inflammatory effects that may prompt novel cell-type-specific CXCR2-directed therapeutics.
5-Methoxyflavone alleviates LPS-mediated lung injury by promoting Nrf2-mediated the suppression of NOX4/TLR4 axis in bronchial epithelial cells and M1 polarization in macrophages.
Liang P, Wang L, Yang S … +6 more , Pan X, Li J, Zhang Y, Liang Y, Li J, Zhou B
J Inflamm (Lond) · 2022 Nov · PMID 36451220 · Full text
BACKGROUND: Acute lung injury (ALI) arises from sepsis or bacterial infection, which are life-threatening respiratory disorders that cause the leading cause of death worldwide. 5-Methoxyflavone, a methylated flavonoid, i...
BACKGROUND: Acute lung injury (ALI) arises from sepsis or bacterial infection, which are life-threatening respiratory disorders that cause the leading cause of death worldwide. 5-Methoxyflavone, a methylated flavonoid, is gaining increased attention for its various health benefits. In the current study, we investigated the potential effects of 5-methoxyflavone against LPS-mediated ALI and elucidated the corresponding possible mechanism. METHODS: A mouse model with ALI was established by intratracheal instillation of LPS, and lung pathological changes, signaling pathway related proteins and apoptosis in lung tissues were estimated by H&E staining, immunofluorescence and TUNEL assay, respectively. Cell viability was evaluated by MTT assay; protein levels of pro-inflammatory mediators were measured by ELISA assay; levels of ROS and M1 macrophage polarization were assayed by flow cytometry; the expression of Nrf2 signaling, NOX4/TLR4 axis and P-STAT1 were detected by western blotting. RESULTS: Our results showed that 5-methoxyflavone treatment inhibited LPS-induced expression of NOX4 and TLR4 as well as the activation of downstream signaling (NF-κB and P38 MAPK), which was accompanied by markedly decreased ROS levels and pro-inflammatory cytokines (IL-6, TNF-α, MCP-1, and IL-8) in BEAS-2B cells. Moreover, we revealed that these effects of 5-methoxyflavone were related to its Nrf2 activating property, and blockade of Nrf2 prevented its inhibitory effects on NOX4/TLR4/NF-κB/P38 MAPK signaling, thus abrogating the anti-inflammatory effects of 5-methoxyflavone. Besides, the Nrf2 activating property of 5-methoxyflavone in RAW264.7 cells led to inhibition of LPS/IFN-γ-mediated STAT1 signaling, resulting in suppression of LPS/IFN-γ-induced M1 macrophage polarization and the repolarization of M2 macrophages to M1. In a mouse model of LPS-induced ALI, 5-methoxyflavone administration ameliorated LPS-mediated lung pathological changes, the increased lung index (lung/body weight ratio), and epithelial cell apoptosis. Meanwhile, we found 5-methoxyflavone effectively suppressed the hyperactive signaling pathways and the production of excessive pro-inflammatory mediators. Moreover, 5-methoxyflavone reduced LPS-mediated M1 macrophage polarization associated with elevated P-STAT1 activation in the lung tissues. In addition, 5-methoxyflavone improved the survival of LPS-challenged mice. CONCLUSION: These results indicated that 5-methoxyflavone might be suitable for the development of a novel drug for ALI therapeutic.
Neutrophil reverse migration.
Xu Q, Zhao W, Yan M … +1 more , Mei H
J Inflamm (Lond) · 2022 Nov · PMID 36424665 · Full text
The behavior of neutrophils is very important for the resolution of inflammation and tissue repair. People have used advanced imaging techniques to observe the phenomenon of neutrophils leaving the injured or inflammator...
The behavior of neutrophils is very important for the resolution of inflammation and tissue repair. People have used advanced imaging techniques to observe the phenomenon of neutrophils leaving the injured or inflammatory site and migrating back into blood vessels in transgenic zebrafish and mice, which is called neutrophil reverse migration. Numerous studies have shown that neutrophil reverse migration is a double-edged sword. On the one hand, neutrophil reverse migration can promote the resolution of local inflammation by accelerating the clearance of neutrophils from local wounds. On the other hand, neutrophils re-enter the circulatory system may lead to the spread of systemic inflammation. Therefore, accurate regulation of neutrophil reverse migration is of great significance for the treatment of various neutrophil- mediated diseases. However, the mechanism of neutrophil reverse migration and its relationship with inflammation resolution is unknown. In this review, we reviewed the relevant knowledge of neutrophil reverse migration to elucidate the potential mechanisms and factors influencing reverse migration and its impact on inflammation in different disease processes.
The antigen CD300e drives T cell inflammation in adipose tissue and elicits an antibody response predictive of the insulin sensitivity recovery in obese patients.
Coletta S, Trevellin E, Benagiano M … +5 more , Romagnoli J, Della Bella C, D'Elios MM, Vettor R, de Bernard M
J Inflamm (Lond) · 2022 Nov · PMID 36419085 · Full text
Obesity and insulin resistance (IR), the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation. Bariatric surgery leads to a considerable reduction in the adipose tiss...
Obesity and insulin resistance (IR), the key features of metabolic syndrome, are closely associated with a state of chronic, low-grade inflammation. Bariatric surgery leads to a considerable reduction in the adipose tissue mass and systemic inflammation along with a reduction of IR, with a whole-body metabolic improvement. However, a sizable portion of people experience an IR relapse within few years of remission.Numerous studies have attempted to explore the best clinical predictors of the improvement of insulin sensitivity and the maintenance of glucose homeostasis after bariatric surgery, but no simple fasting blood test has been found to be effective in predicting the short and long-term beneficial effects on glycaemia.With the present study, we investigated T-cell and antibody responses against CD300e, an antigen highly expressed in the adipose tissue of patients with obesity before the bariatric surgery-induced weight loss. We found both in fat tissue and in peripheral blood anti-CD300e-specific T helper 1 responses. Moreover, we evidenced in the sera of individuals with obesity an antibody response towards CD300e and revealed the existence of a significant correlation between the level of antibodies before surgery and the maintenance of glucose control after the intervention.
Protein arginine deiminase 2 (PAD2) modulates the polarization of THP-1 macrophages to the anti-inflammatory M2 phenotype.
Stachowicz A, Pandey R, Sundararaman N … +3 more , Venkatraman V, Van Eyk JE, Fert-Bober J
J Inflamm (Lond) · 2022 Nov · PMID 36401289 · Full text
BACKGROUND: Macrophages are effector cells of the innate immune system that undergo phenotypical changes in response to organ injury and repair. These cells are most often classified as proinflammatory M1 and anti-inflam...
BACKGROUND: Macrophages are effector cells of the innate immune system that undergo phenotypical changes in response to organ injury and repair. These cells are most often classified as proinflammatory M1 and anti-inflammatory M2 macrophages. Protein arginine deiminase (PAD), which catalyses the irreversible conversion of protein-bound arginine into citrulline, is expressed in macrophages. However, the substrates of PAD and its role in immune cells remain unclear. This study aimed to investigate the role of PAD in THP-1 macrophage polarization to the M1 and M2 phenotypes and identify the citrullinated proteins and modified arginines that are associated with this biological switch using mass spectrometry. RESULTS: Our study showed that PAD2 and, to a lesser extent, PAD1 and PAD4 were predominantly expressed in M1 macrophages. We showed that inhibiting PAD expression with BB-Cl-amidine decreased macrophage polarization to the M1 phenotype (TNF-α, IL-6) and increased macrophage polarization to the M2 phenotype (MRC1, ALOX15). This process was mediated by the downregulation of proteins involved in the NF-κβ pathway. Silencing PAD2 confirmed the activation of M2 macrophages by increasing the antiviral innate immune response and interferon signalling. A total of 192 novel citrullination sites associated with inflammation, cell death and DNA/RNA processing pathways were identified in M1 and M2 macrophages. CONCLUSIONS: We showed that inhibiting PAD activity using a pharmacological inhibitor or silencing PAD2 with PAD2 siRNA shifted the activation of macrophages towards the M2 phenotype, which can be crucial for designing novel macrophage-mediated therapeutic strategies. We revealed a major citrullinated proteome and its rearrangement following macrophage polarization, which after further validation could lead to significant clinical benefits for the treatment of inflammation and autoimmune diseases.
Induction of pyroptotic cell death as a potential tool for cancer treatment.
Faria SS, Fernando AJ, de Lima VCC … +3 more , Rossi AG, de Carvalho JMA, Magalhães KG
J Inflamm (Lond) · 2022 Nov · PMID 36376979 · Full text
Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, an...
Cancer is a complex pathological disease and the existing strategies for introducing chemotherapeutic agents have restricted potential due to a lack of cancer cell targeting specificity, cytotoxicity, bioavailability, and induction of multi-drug resistance. As a prospective strategy in tackling cancer, regulating the inflammatory pyroptosis cell death pathway has been shown to successfully inhibit the proliferation and metastasis of various cancer cell types. Activation of inflammasomes such as the NLRP3 results in pyroptosis through cleavage of gasdermins, which forms pores in the cell membranes, inducing membrane breakage, cell rupture, and death. Furthermore, pyroptotic cells release pro-inflammatory cytokines such as IL-1β and IL-18 along with various DAMPs that prime an auxiliary anti-tumor immune response. Thus, regulation of pyroptosis in cancer cells is a way to enhance their immunogenicity. However, immune escape involving myeloid-derived suppressor cells has limited the efficacy of most pyroptosis-based immunotherapy strategies. In this review, we comprehensively summarize the cellular and molecular mechanisms involved in the inflammasome-mediated pyroptosis pathways in cancer cells, exploring how it could modulate the tumor microenvironment and be beneficial in anti-cancer treatments. We discuss various existing therapeutic strategies against cancer, including immunotherapy, oncolytic virus therapy, and nanoparticle-based therapies that could be guided to trigger and regulate pyroptosis cell death in cancer cells, and reduce tumor growth and spread. These pyroptosis-based cancer therapies may open up fresh avenues for targeted cancer therapy approaches in the future and their translation into the clinic.
Extracellular vesicles isolated from hyperuricemia patients might aggravate airway inflammation of COPD via senescence-associated pathway.
Liu X, Li Z, Zheng Y … +6 more , Wang W, He P, Guan K, Wu T, Wang X, Zhang X
J Inflamm (Lond) · 2022 Nov · PMID 36324164 · Full text
BACKGROUNDS: Chronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD a...
BACKGROUNDS: Chronic obstructive pulmonary disease (COPD) is a major health issue resulting in significant mortality worldwide. Due to the high heterogeneity and unclear pathogenesis, the management and therapy of COPD are still challenging until now. Elevated serum uric acid(SUA) levels seem to be associated with the inflammatory level in patients with COPD. However, the underlying mechanism is not yet clearly established. In the current research, we aim to elucidate the effect of high SUA levels on airway inflammation among COPD patients. METHODS: Through bioinformatic analysis, the common potential key genes were determined in both COPD and hyperuricemia (HUA) patients. A total of 68 COPD patients aged 50-75-year were included in the study, and their clinical parameters, including baseline characteristics, lung function test, as well as blood chemistry test were recorded. These parameters were then compared between the COPD patients with and without HUA. Hematoxylin & Eosin (HE), immunofluorescence (IF), and Masson trichrome staining were performed to demonstrate the pathological changes in the lung tissues. Furthermore, we isolated extracellular vesicles (EVs) from plasma, sputum, and bronchoalveolar lavage fluid (BALF) samples and detected the expression of inflammatory factor (Interleukin-6 (IL-6), IL-8 and COPD related proteases (antitrypsin and elastase) between two groups. Additionally, we treated the human bronchial epithelial (HBE) cells with cigarette smoke extract (CSE), and EVs were derived from the plasma in vitro experiments. The critical pathway involving the relationship between COPD and HUA was eventually validated based on the results of RNA sequencing (RNA-seq) and western blot (WB). RESULTS: In the study, the COPD patients co-existing with HUA were found to have more loss of pulmonary function compared with those COPD patients without HUA. The lung tissue samples of patients who had co-existing COPD and HUA indicated greater inflammatory cell infiltration, more severe airway destruction and even fibrosis. Furthermore, the high SUA level could exacerbate the progress of airway inflammation in COPD through the transfer of EVs. In vitro experiments, we determined that EVs isolated from plasma, sputum, and BALF played pivotal roles in the CSE-induced inflammation of HBE. The EVs in HUA patients might exacerbate both systemic inflammation and airway inflammatory response via the senescence-related pathway. CONCLUSION: The pulmonary function and clinical indicators of COPD patients with HUA were worse than those without HUA, which may be caused by the increased airway inflammatory response through the EVs in the patient's peripheral blood. Moreover, it might mediate the EVs via senescence-related pathways in COPD patients with HUA.
Disulfiram alleviates acute lung injury and related intestinal mucosal barrier impairment by targeting GSDMD-dependent pyroptosis.
Zhao J, Wang H, Zhang J … +4 more , Ou F, Wang J, Liu T, Wu J
J Inflamm (Lond) · 2022 Oct · PMID 36266722 · Full text
BACKGROUND: Pyroptosis was implicated in acute lung injury (ALI). Disulfiram is reported as an effective pyroptosis inhibitor by inhibiting gasdermin D(GSDMD). However, the function of pyroptosis executor GSDMD and treat...
BACKGROUND: Pyroptosis was implicated in acute lung injury (ALI). Disulfiram is reported as an effective pyroptosis inhibitor by inhibiting gasdermin D(GSDMD). However, the function of pyroptosis executor GSDMD and treatment of disulfiramon on ALI, especially whether it was involved in ALI-associated intestinal mucosal barrier impairment remains unclear. This study aims to explore the role of pyroptosis and disulfiram' treatment on ALI and related intestinal mucosal barrier impairment. METHODS: First, we established lipopolysaccharide (LPS)-induced ALI models in wild-type and Gsdmd knockout (Gsdmd), to detect the effect of pyroptosis on ALI-related intestinal mucosal barrier impairment. Furthermore, we used wild-type mice treated with disulfiram to investigate the treatment of disulfiram on ALI and related intestinal mucosal barrier impairment. RESULTS: The data showed that GSDMD-mediated pyroptosis was activated in both lung and intestinal mucosa tissues in LPS-induced ALI, and deficiency of Gsdmd ameliorated LPS-induced ALI and related intestinal mucosal barrier damage. We also disclosed that disulfiram inhibited the pyroptosis level, and alleviated ALI and related intestinal mucosal barrier impairment induced by LPS. CONCLUSION: These findings suggested the role of GSDMD-mediated pyroptosis and the potential application treatment of disulfiram in ALI and related intestinal mucosal barrier damage.
Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response in mice.
Yin H, Feng Y, Duan Y … +3 more , Ma S, Guo Z, Wei Y
J Inflamm (Lond) · 2022 Oct · PMID 36253774 · Full text
BACKGROUND: Chronic inflammation and oxidant/antioxidant imbalance are two main pathological features associated with lipopolysaccharide (LPS)-induced acute lung injury (ALI). The following study investigated the protect...
BACKGROUND: Chronic inflammation and oxidant/antioxidant imbalance are two main pathological features associated with lipopolysaccharide (LPS)-induced acute lung injury (ALI). The following study investigated the protective role of hydrogen (H), a gaseous molecule without known toxicity, in LPS-induced lung injury in mice and explored its potential molecular mechanisms. METHODS: Mice were randomly divided into three groups: H control group, LPS group, and LPS + H group. The mice were euthanized at the indicated time points, and the specimens were collected. The 72 h survival rates, cytokines contents, pathological changes, expression of Toll-like receptor 4 (TLR4), and oxidative stress indicators were analyzed. Moreover, under different culture conditions, RAW 264.7 mouse macrophages were used to investigate the potential molecular mechanisms of H in vitro. Cells were divided into the following groups: PBS group, LPS group, and LPS + H group. The cell viability, intracellular ROS, cytokines, and expression of TLR4 and nuclear factor kappa-B (NF-κB) were observed. RESULTS: Hydrogen inhalation increased the survival rate to 80%, reduced LPS-induced lung damage, and decreased inflammatory cytokine release in LPS mice. Besides, H showed remarked anti-oxidative activity to reduce the MDA and NO contents in the lung. In vitro data further indicated that H down-regulates the levels of ROS, NO, TNF-α, IL-6, and IL-1β in LPS-stimulated macrophages and inhibits the expression of TLR4 and the activation of nuclear factor kappa-B (NF-κB). CONCLUSION: Hydrogen gas alleviates lipopolysaccharide-induced acute lung injury and inflammatory response most probably through the TLR4-NF-κB pathway.
Retraction Note: Impact of NF-κB pathway on the intervertebral disc inflammation and degeneration induced by over-mechanical stretching stress.
Xu H, Qi G, Li K … +3 more , Yang K, Luo D, Cai Z
J Inflamm (Lond) · 2022 Oct · PMID 36217180 · Full text
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Deeper insight into the role of IL-17 in the relationship beween hypertension and intestinal physiology.
Yang ZJ, Wang TT, Wang BY … +6 more , Gao H, He CW, Shang HW, Lu X, Wang Y, Xu JD
J Inflamm (Lond) · 2022 Oct · PMID 36195874 · Full text
With the incidence of hypertension increasing worldwide, more and more the mechanisms of hypertension from the perspective of immunity have found. Intestinal microbiota as well as its metabolites relationship with hypert...
With the incidence of hypertension increasing worldwide, more and more the mechanisms of hypertension from the perspective of immunity have found. Intestinal microbiota as well as its metabolites relationship with hypertension has attracted great attention from both clinicians and investigators. However, the associations of hypertension with lesions of a large number of immune factors including IL-17, MCP-1, IL-6, TGF-β, IL-10 and others have not been fully characterized. In this review, after introducing the immune factors as the most potent anti/pro-hypertension agents known, we provide detailed descriptions of the IL-17 involved in the pathology of hypertension, pointing out the underlying mechanisms and suggesting the clinical indications.
Single-cell RNA-seq data analysis characterizing bronchoalveolar epithelial cells in patients with SARS-CoV-2 infection.
Deng Z, Li Q, Li Y … +7 more , Deng Z, Chen X, Zhao Z, Wang G, Wang D, Liu J, Li W
J Inflamm (Lond) · 2022 Sep · PMID 36064702 · Full text
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been reported to be the main receptor for SARS-CoV-2 infection of host cells. Understanding the changes in bronchoalveolar epithelial cells after SARS-CoV-2 infectio...
BACKGROUND: Angiotensin-converting enzyme 2 (ACE2) has been reported to be the main receptor for SARS-CoV-2 infection of host cells. Understanding the changes in bronchoalveolar epithelial cells after SARS-CoV-2 infection of host cells and the intercellular communication relationship between these epithelial cell changes and immune cells is of great significance for the development of therapeutic methods. METHODS: We explored the single-cell RNA sequence (scRNA-seq) of cells infected with bronchoalveolar lavage fluid (BaLF) of patients with different severities of SARS-CoV-2 and healthy people. RESULTS: We found 11 clusters of epithelial cells in the BaLF, and they were derived from the S group. In the S group, the proportion of cells with positive ACE2 expression was relatively high. ACE2 was relatively more expressed in epithelial cell clusters 1, 3, and 7. Clusters 4 and 5 represented the original state, and there were two differentiation directions: one was cluster 2, and the others were clusters 1, 3, and 6. Cluster 7 was the intermediate state. Clusters 1, 3, 6, and 7 had high similarities (> 0.9), and their main signaling pathways focused on inflammatory activation and immune response. Cluster 2 was relatively specific and was up-regulated in differential genes that were mainly related to apoptosis. The ligand-receptor expression pattern of TNFRSF10D-TNFSF10 showed a special inter-cell regulatory relationship between epithelial cell cluster 2 and macrophages. CONCLUSION: This study revealed the changes in epithelial cells derived from alveolar lavage fluid after SARS-CoV-2 infection and the communication relationship with other immune cells.
SILAC-based quantitative proteomics to investigate the eicosanoid associated inflammatory response in activated macrophages.
Brace N, Megson IL, Rossi AG … +2 more , Doherty MK, Whitfield PD
J Inflamm (Lond) · 2022 Sep · PMID 36050729 · Full text
BACKGROUND: Macrophages play a central role in inflammation by phagocytosing invading pathogens, apoptotic cells and debris, as well as mediating repair of tissues damaged by trauma. In order to do this, these dynamic ce...
BACKGROUND: Macrophages play a central role in inflammation by phagocytosing invading pathogens, apoptotic cells and debris, as well as mediating repair of tissues damaged by trauma. In order to do this, these dynamic cells generate a variety of inflammatory mediators including eicosanoids such as prostaglandins, leukotrienes and hydroxyeicosatraenoic acids (HETEs) that are formed through the cyclooxygenase, lipoxygenase and cytochrome P450 pathways. The ability to examine the effects of eicosanoid production at the protein level is therefore critical to understanding the mechanisms associated with macrophage activation. RESULTS: This study presents a stable isotope labelling with amino acids in cell culture (SILAC) -based proteomics strategy to quantify the changes in macrophage protein abundance following inflammatory stimulation with Kdo2-lipid A and ATP, with a focus on eicosanoid metabolism and regulation. Detailed gene ontology analysis, at the protein level, revealed several key pathways with a decrease in expression in response to macrophage activation, which included a promotion of macrophage polarisation and dynamic changes to energy requirements, transcription and translation. These findings suggest that, whilst there is evidence for the induction of a pro-inflammatory response in the form of prostaglandin secretion, there is also metabolic reprogramming along with a change in cell polarisation towards a reduced pro-inflammatory phenotype. CONCLUSIONS: Advanced quantitative proteomics in conjunction with functional pathway network analysis is a useful tool to investigate the molecular pathways involved in inflammation.
Human monocytes differentiate into tumor-associated macrophages upon SKOV3 cells coculture and/or lysophosphatidic acid stimulation.
Feng Y, Xiao M, Cao G … +9 more , Liu H, Li Y, Wang S, Zijtveld S, Delvoux B, Xanthoulea S, Romano A, Liu C, Zhang Z
J Inflamm (Lond) · 2022 Jul · PMID 35842650 · Full text
BACKGROUND: Serous ovarian carcinoma is the most common type of ovarian carcinoma. Tumor-associated macrophages (TAMs) promote ovarian cancer progression. Most macrophages are generated by monocyte differentiation. Lysop...
BACKGROUND: Serous ovarian carcinoma is the most common type of ovarian carcinoma. Tumor-associated macrophages (TAMs) promote ovarian cancer progression. Most macrophages are generated by monocyte differentiation. Lysophosphatidic acid (LPA) levels are high in blood, tissues and ascites of patients with ovarian cancer. This study investigated whether human monocytes can directly differentiate into TAMs in the serous ovarian carcinoma microenvironment. METHODS: Human monocytes were isolated and purified from umbilical cord blood. A serous ovarian carcinoma-like microenvironment was generated by coculturing monocytes and SKOV3 cells in 0.4-μm-pore-size Transwell chambers. Additionally, the effect of LPA was assessed. The two cultured cell types and supernatants were evaluated. RESULTS: The morphology and function of monocytes cocultured with SKOV3 cells and/or stimulated with LPA were significantly changed compared with those of non-stimulated monocytes. The CD14 + CD163 + and CD206 + phenotype indicated that stimulated cells were TAMs. The induced cells promoted SKOV3 cell proliferation and invasion, further proving that they were TAMs. The level of the cytokine interleukin-6R in the supernatant was significantly elevated in the treatment groups compared to the control monocyte group. Pathway enrichment analysis of ELISA results showed a strong influence of interleukin-6 family signaling, especially the JAK-STAT signaling pathway, further confirming the importance of IL-6R. CONCLUSION: Monocytes can differentiate into TAMs under coculture with SKOV3 cells and/or LPA stimulation. The induced TAMs promote SKOV3 cell proliferation and invasion. The cytokine receptor IL-6sR and the JAK-STAT signaling pathway play an important role in the differentiation of monocytes into TAMs.
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