Pulmonary Inflammatory Infiltration Research Articles

The preventative effects of Lactococcus Lactis metabolites against LPS-induced sepsis.

Sepsis is a syndrome of organ dysfunction caused by a dysregulated host response to infection and septic shock. Currently, antibiotic therapy is the standard treatment for sepsis, but it can lead to drug resistance. The disturbance of the gut microbiota which is affected by sepsis could lead to the development of organ failure. It is reported that probiotics could shape the gut microbiota, potentially controlling a variety of intestinal diseases and promoting whole-body health. In this study, we evaluated the preventive effects of intra- and extracellular products of probiotics on sepsis. The extracellular products of Lactococcus lactis (L. lactis) were identified through the in vivo cell experiments. The preventive effect and mechanism of L. lactis extracellular products on mouse sepsis were further explored through HE staining, mouse survival rate measurement, chip analysis, etc. L. lactis extracellular products increase cell survival and significantly reduce inflammatory factors secreted in a cellular sepsis model. In in vivo experiments in mice, our samples attenuated sepsis-induced pulmonary edema and inflammatory infiltrates in the lungs of mice, and reduced mortality and inflammatory factor levels within the serum of mice. Finally, the mechanism of sepsis prevention by lactic acid bacteria is suggested. Extracellular products of L. lactis could effectively prevent sepsis episodes. In animal experiments, we reported that extracellular products of L. lactis can effectively prevent sepsis, and preliminarily discussed the pathological mechanism, which provides more ideas for the prevention of sepsis. In the future, probiotics may be considered a new way to prevent sepsis.

Investigation of Metabolic and Inflammatory Disorder in the Aging FGF21 Knockout Mouse.

Aging is a physiological condition accomplished with persistent low-grade inflammation and metabolic disorders. FGF21 has been reported to act as a potent longevity determinant, involving inflammatory response and energy metabolism. In this study, we engineered aging FGF21 knockout mice of 36-40weeks and observed that FGF21 deficiency manifests a spontaneous inflammatory response of lung and abnormal accumulation of lipids in liver. On one hand, inflamed state in lungs and increased circulating inflammatory cytokines were found in FGF21 knockout mice of 36-40weeks. To evaluate the ability of FGF21 to suppress inflammation, a subsequent study found that FGF21 knockout aggravated LPS-induced pulmonary exudation and inflammatory infiltration in mice, while exogenous administration of FGF21 reversed these malignant phenotypes by enhancing microvascular endothelial junction. On the other hand, FGF21 knockout induces fatty liver in aging mice, characterized by excessive accumulation of triglycerides within hepatocytes. Further quantitative metabolomics and lipidomics analysis revealed perturbed metabolic profile in liver lacking FGF21, including disrupted glucose and lipids metabolism, glycerophospholipid metabolism, and amino acid metabolism. Taken together, this investigation reveals the protective role of FGF21 during aging by weakening the inflammatory response and balancing energy metabolism.

Ophiopogonin D alleviates acute lung injury by regulating inflammation via the STAT3/A20/ASK1 axis

BackgroundAcute lung injury (ALI) is characterized by acute pulmonary inflammatory infiltration. Alveolar epithelial cells (AECs) release numerous pro-inflammatory cytokines, which result in the pathological changes seen in ALI. Ophiopogonin D (OD), extracted from the roots of Ophiopogon japonicus (Thunb.) Ker Gawl. (Liliaceae), reduces inflammation; however, the efficacy of OD in ALI has not been reported and the underlying molecular mechanisms remain unclear. PurposeThis study investigated the anti-inflammatory effects of OD, as well as the underlying mechanisms, in AECs and a mouse ALI model. MethodsLipopolysaccharide (LPS) and tumor necrosis factor-α (TNF-α) were used to stimulate macrophages and A549 cells, and a mouse ALI model was established by intratracheal LPS administration. The anti-inflammatory effects and mechanisms of OD in the TNF-α-induced in vitro inflammation model was evaluated using real-time quantitative polymerase chain reaction qPCR), enzyme-linked immunosorbent assay (ELISA), western blotting, nuclear and cytoplasmic protein extraction, and immunofluorescence. The in vivo anti-inflammatory activity of OD was evaluated using hematoxylin and eosin staining, qPCR, ELISA, and western blotting. ResultsThe bronchoalveolar lavage fluid and lung tissue of LPS-induced ALI mice exhibited increased TNF-α expression. TNF-α induced a significantly greater pro-inflammatory effect in AECs than LPS. OD reduced inflammation and mitogen-activated protein kinase (MAPK) and transcription factor p65 phosphorylation in vivo and in vitro and promoted signal transducer and activator of transcription 3 (STAT3) phosphorylation and A20 expression, thereby inducing apoptosis signal-regulating kinase 1 (ASK1) proteasomal degradation. ConclusionOD exerts an anti-inflammatory effect by promoting STAT3-dependent A20 expression and ASK1 degradation. OD may therefore have therapeutic value in treating ALI and other TNF-α-related inflammatory diseases.

Therapeutic Effect and Safety Evaluation of Naringin on Klebsiella pneumoniae in Mice

Critically ill patients with Corona Virus Disease 2019 (COVID-19) often develop secondary bacterial infections that pose a significant threat to patient life safety, making the development of drugs to prevent bacterial infections in the lungs critical to clinical care. Naringin (NAR) is one of the significant natural flavonoids rich in Pummelo Peel (Hua Ju Hong), with anti-inflammatory, antimicrobial, and antioxidant activities, and is commonly used in treating respiratory tract infectious diseases. In this study, the in vitro and in vivo findings revealed that, after Klebsiella pneumoniae (Kpn) infection, NAR inhibited overactivation of the nuclear factor kappa-B(NF-κB) signaling pathway in alveolar macrophages of mice, reduced neutrophil (NEs) recruitment, and lowered the induced production of proinflammatory markers, such as Interleukin-6(IL-6) and tumor necrosis factor α(TNF-α). Thus, it suppressed excessive immune responses in the lungs, as well as attenuated the induced pulmonary fibrosis and inflammatory infiltrates. These results suggest that NAR has a preventive effect against Kpn in mice. In addition, the study evaluated NAR’s potential toxicity, demonstrating that NAR is safe at effective doses. These results suggested that NAR effectively reduces excessive inflammatory damage in the lungs induced by Kpn and enhances the body’s ability to clear bacteria. Therefore, NAR may be an effective and safe healthcare drug for preventing and caring for bacterial pneumonia.

Sequential inspiratory muscle exercise-noninvasive positive pressure ventilation alleviates oxidative stress in COPD by mediating SOCS5/JAK2/STAT3 pathway

BackgroundPulmonary rehabilitation training is of great significance for the prognosis of chronic obstructive pulmonary disease (COPD) patients. The purpose of this study was to investigate the therapeutic effect and pathway of a new sequential noninvasive positive pressure ventilation (NIPPV) + inspiratory muscle training (IMT) therapy.MethodsA total of 100 COPD patients were enrolled and randomly divided into oxygen therapy (OT), NIPPV, IMT and sequential (NIPPV + IMT) group. Lung function, exercise endurance, quality of life, and dyspnea symptoms were examined and recorded. Then, reactive oxygen species (ROS), malonaldehyde (MDA), superoxide dismutase (SOD) and glutathione (GSH) levels were detected by enzyme-linked immunoassay, and suppressor of cytokine signaling 5 (SOCS5)/janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3) pathway expression changes were detected by quantitative real time-polymerase chain reaction (qRT-PCR) and western blot. A mouse model of COPD was then established to further verify the effects of SOCS5/JAK2/STAT3 pathways on lung function and oxidative stress.ResultsAfter 8 weeks of treatment, NIPPV, IMT or sequential (NIPPV + IMT) significantly improved exercise endurance, quality of life and dyspnea, reduced oxidative stress, promoted SOCS5 expression and inhibited the activation of JAK2/STAT3 pathway, and no significant effect was observed on lung function of COPD patients. Notably, sequential (NIPPV + IMT) showed better therapeutic outcomes than either IMT or NIPPV alone. Moreover, results at the animal level showed that overexpression of SOCS5 significantly reduced pulmonary inflammatory infiltration, pathological changes and oxidative stress levels in COPD mice, enhanced lung function, and inhibited the activation of JAK2/STAT3 pathway.ConclusionOur results elucidated that sequential (NIPPV + IMT) significantly relieved COPD development by regulating SOCS5/JAK2/STAT3 signaling-mediated oxidative stress.

A natural sesquiterpene lactone isolinderalactone attenuates lipopolysaccharide-induced inflammatory response and acute lung injury through inhibition of NF-κB pathway and activation Nrf2 pathway in macrophages

Isolinderalactone is the main sesquiterpene lactone isolated from Lindera aggregata, a traditional Chinese medicine widely used to treat pain and inflammation. Although isolinderalactone has been demonstrated to possess anti-cancer effect, its anti-inflammatory activity and underlying mechanism has not been well characterized. Herein, isolinderalactone was able to significantly inhibit the production of NO and PGE2 by reducing the expressions of iNOS and COX2 in LPS-stimulated RAW264.7 macrophages and BMDMs, and decreased the mRNA levels of IL-1β, IL-6, and TNF-α in LPS-induced RAW264.7 cells. In vivo, isolinderalactone effectively alleviated LPS-induced acute lung injury (ALI), which manifested as reduction in pulmonary inflammatory infiltration, myeloperoxidase activity, and production of PGE2, IL-1β, IL-6, TNF-α, and malondialdehyde. Furthermore, isolinderalactone inhibited phosphorylation of IKKα/β, phosphorylation and degradation of IκBα, and nuclear translocation of NF-κB p65, thereby blocking NF-κB pro-inflammatory pathway. Meanwhile, isolinderalactone reduced the intracellular ROS through promoting the activation of Nrf2-HMOX1 antioxidant axis. By using drug affinity responsive target stability assay and molecular docking, isolinderalactone was found to covalently interact with IKKα/β and Keap1, which may contribute to its anti-inflammatory action. Additionally, a thiol donor β-mercaptoethanol significantly abolished isolinderalactone-mediated anti-inflammatory action in vitro, indicating the crucial role of the unsaturated lactone of isolinderalactone on its anti-inflammatory effects. Taken together, isolinderalactone protected against LPS-induced ALI in mice, which may be associated with its inhibition of NF-κB pathway and activation of Nrf2 signaling in macrophages.

Interleukin-41 diminishes cigarette smoke-induced lung inflammation in mice

BackgroundChronic obstructive pulmonary disease (COPD) and other inflammatory lung illnesses are markedly exacerbated by cigarette smoke (CS). The novel cytokine interleukin (IL)-41 has immunoregulatory effects, but data on its function in lung inflammation caused by CS are limited and inconclusive. Our study aimed to investigate the ability of IL-41 to protect against CS-induced lung inflammation in vivo. MethodsIn this model, mice were exposed to six cigarettes three times daily for 1 h, with 4-hour intervals between exposures, for 5 consecutive days. Mice received an intraperitoneal dose of IL-41 or a negative control 1 day prior to their initial exposure to CS. On day 6, mice were sacrificed to assess the impact of IL-41 on CS-induced lung inflammation. ResultsWe found that IL-41 pre-treatment alleviated pulmonary inflammatory infiltration and lung tissue lesions. IL-41 pre-treatment also limited CS-induced weight loss, and resulted in lower numbers of macrophages in the bronchoalveolar lavage fluid and lower percentages of neutrophils and monocytes in the blood. Furthermore, it promoted the polarization of M2 macrophages rather than M1 macrophages, as determined by immunohistochemistry. Consistent with its effects on M2 polarization, pre-treatment with IL-41 was associated with higher levels of IL-10 in the bronchoalveolar lavage fluid and lung tissues of CS-exposed animals and lower production of tumor necrosis factor-α, IL-6 and IL-1β in the serum and lung tissues. ConclusionsThese findings suggest that IL-41 could be used therapeutically to treat CS-induced lung inflammatory disorders as it inhibits CS-induced pulmonary inflammation when administered in vivo in mice.

Inhaled braylin regulates Th2 response and induces relaxant effects in the airway muscles in a model of ovalbumin-induced asthma

BackgroundCoumarins are compounds with wide and relevant pharmacological properties, being considered one of the most important chemical classes among natural compounds. Braylin (6-methoxyseselin) is a coumarin whose pharmacological properties have not yet been extensively explored. Previous studies have shown its anti-inflammatory and immunomodulatory activities, potentially associated with glucocorticoid receptors, plus it is a phosphodiesterase 4 inhibitor. Thus, the present study was designed to investigate the pharmacological potential of braylin for asthma treatment. MethodsMice induced to an asthma model using ovalbumin (OVA) were treated with vehicle, braylin, or dexamethasone via intraperitoneal injection or inhalation, and the bronchoalveolar lavage (BAL) was collected to evaluate infiltration of inflammatory cells, and cytokine levels. Histopathological and morphometric analysis of lung tissue were also conducted, while ex vivo isometric measurement assessed the effect of braylin on tracheal relaxation. ResultsBraylin (50 mg/kg) showed similar efficacy in reducing the total count of inflammatory cells in the BAL of asthmatic mice by inhalation or intraperitoneal route. Inhaled braylin reduced, in a dose-dependent manner (25 to 100 mg/kg), the total count of inflammatory cells in the BAL of OVA-induced mice, more specifically eosinophils and neutrophils. Plus, inhaled braylin reduced the BAL levels of IL-4, IL-5, and IL-13, cytokines involved in asthma Th2 response. It also reduced pulmonary inflammatory infiltrate and the occurrence of goblet cell metaplasia. In a set of ex vivo assays, braylin was able to induce concentration-dependent relaxation of the trachea from mice with or without OVA-induced asthma. ConclusionsThe present results suggest that braylin may be a promising candidate for the treatment of asthma by regulating the Th2 response, inducing relaxant effects in the airway muscles, and presenting efficacy by inhalation route.

Irisin attenuates fine particulate matter induced acute lung injury by regulating Nod2/NF-κB signaling pathway

Air pollution consisting of fine particulate matter (PM2.5) can induce or aggravate pulmonary inflammatory injury. Irisin has been shown to inhibit inflammation and help to protect against acute kidney, lung or brain injury. However, the role of irisin in lung inflammation after exposure to PM2.5 remains unclear. The aim of this study was to investigate the effect and molecular mechanism of irisin supplementation on in vitro and in vivo models of PM2.5-induced acute lung injury（ALI). C57BL/6 mice and alveolar macrophage cell line (MH-S) were treated with PM2.5. Histopathological examination and FNDC5/ irisin immunofluorescence staining was performed on lung tissue sections. MH-S cell viability was determined by CCK-8 assay. The levels of Nod2, NF-κB p65 and NLRP3 were detected by qRT-PCR and western blotting. The levels of cytokines (IL-1β, IL-18 and TNF-α) were detected by ELISA. PM2.5 exposure induced increased secretion of pro-inflammatory factors and activation of Nod2, NF-κB p65 and NLRP3 as well as endogenous levels of irisin. In vivo and in vitro inflammation was alleviated by irisin supplementation. Irisin significantly decreased IL-1β, IL-18, and TNF-α production at both mRNA and protein level. Expression levels of Nod2, NF-κB p65, and NLRP3 were all significantly affected by irisin. In vivo the degree of pulmonary injury and inflammatory infiltration was weakened after irisin administration. In vitro, irisin could inhibit the activation of the NLRP3 inflammasome for a sustained period of 24 h, and its inhibitory ability was gradually enhanced. In conclusion, our findings indicate that irisin can modulate the inflammatory injury of lung tissue caused by PM2.5 through the Nod2/NF-κB signaling pathway, suggesting that irisin can be a candidate for the therapeutic or preventive intervention in acute lung inflammation.

Up-regulation of PPAR-γ involved in the therapeutic effect of icariin on cigarette smoke-induced inflammation

Icariin (ICA) might be a potential anti-inflammatory medication in a variety of diseases including COPD, and previous studies showed that ICA could attenuate cigarette smoke (CS)-induced inflammation by inhibiting nuclear factor (NF)-κB. Peroxisome proliferator-activated receptor (PPAR) γ, a nuclear hormone receptor, has been reported to play a critical role in the inflammatory process in COPD. Whether PPAR-γ is involved in the anti-inflammatory effect of icariin on COPD has scarcely been explored. This study aimed at investigating the role of ICA in PPAR-γ expression in the CS-induced model, and then elucidating the therapeutic effects of ICA on COPD based on the PPARγ–NF–κB signaling pathway. The Beas-2B cells and H292 cells were induced with cigarette smoke extract (CSE) for 8 h after treatment with ICA for 16 h. The PPARγ expression and NF-κB pathway-related indicators were detected by western blotting, cellular immunofluorescence, and Real-time PCR. The PPARγ knock down or T0070907-treated Beas-2B cells were constructed to further investigate the relationship between the inhibition of NF-κB by ICA and PPARγ. A COPD model was established by CS exposure for 6 months, and ICA (40 mg/kg) was administrated by gastric perfusion. Then, the pulmonary function, lung histology, inflammatory cytokine levels, and protein expressions were detected. We found ICA up-regulated PPARγ protein expression in both Beas-2B cells and H292 cells, and it improved CSE-induced PPARγ down regulation and NF-κB activation. Furthermore, the inhibition of NF-κB pathway by ICA was partially dependent on PPARγ in the PPARγ knock down or T0070907-treated Beas-2B cells, suggesting that ICA attenuated CSE-induced inflammatory responses were associated with modulating the PPARγ–NF–κB pathway. Moreover, ICA showed similar effects on PPARγ and NF-κB expressions in the COPD model, and it effectively ameliorated the pulmonary function and lung inflammatory infiltration in the COPD rat model. Conclusively, the therapeutic effect of ICA on COPD was indirectly achieved by reducing airway inflammation, which was partially associated with modulating the PPARγ–NF–κB signaling pathway.

Cryptotanshinone attenuates LPS-induced acute lung injury by regulating metabolic reprogramming of macrophage.

Acute lung injury (ALI) is a life-threatening inflammatory disease without effective therapeutic regimen. Macrophage polarization plays a key role in the initiation and resolution of pulmonary inflammation. Therefore, modulating macrophage phenotype is a potentially effective way for acute lung injury. Cryptotanshinone (CTS) is a lipophilic bioactive compound extracted from the root of Salvia miltiorrhiza with a variety of pharmacological effects, especially the anti-inflammatory role. In this study, we investigated the therapeutic and immunomodulatory effects of CTS on ALI. The rat model of ALI was established by intratracheal instillation of LPS (5 mg/kg) to evaluate the lung protective effect of CTS in vivo and to explore the regulation of CTS on the phenotype of lung macrophage polarization. LPS (1 μg/mL) was used to stimulate RAW264.7 macrophages in vitro to further explore the effect of CTS on the polarization and metabolic reprogramming of RAW264.7 macrophages and to clarify the potential mechanism of CTS anti-ALI. CTS significantly improved lung function, reduced pulmonary edema, effectively inhibited pulmonary inflammatory infiltration, and alleviated ALI. Both in vivo and in vitro results revealed that CTS inhibited the differentiation of macrophage into the M1 phenotype and promoted polarization into M2 phenotype during ALI. Further in vitro studies indicated that CTS significantly suppressed LPS-induced metabolic transition from aerobic oxidation to glycolysis in macrophages. Mechanistically, CTS blocked LPS-induced metabolic transformation of macrophages by activating AMPK. These findings demonstrated that CTS regulates macrophage metabolism by activating AMPK, and then induced M1-type macrophages to transform into M2-type macrophages, thereby alleviating the inflammatory response of ALI, suggesting that CTS might be a potential anti-ALI agent.

Sphingosine-1-Phosphate Receptor 4 Attenuates Neutrophilic Airway Inflammation in Experimental Asthma via Repressing Proinflammatory Macrophage Activation.

Patients with eosinophilic asthma react well to conventional treatment of asthma while individualized therapy for non-eosinophilic endotypes have yet to be developed. Dysregulated sphingosine metabolites are associated with the pathophysiology of different asthma endotypes with their receptors involved. However, whether the sphingosine-1-phosphate receptor 4 (S1PR4) contributes to disease progression of asthma remains underappreciated. In this study, we demonstrated that sphingosine metabolism was disturbed in asthma while it could not be used to distinguish between different endotypes of asthma. S1PR4, a vital receptor of bioactive sphingosine metabolites and mainly expressed in macrophages, exhibited lower expression both in patients and experimental mice with neutrophilic airway inflammation. Additionally, S1pr4 deficiency aggravated the OVA/LPS-induced pulmonary inflammation in mice along with a significant up-regulation in M1 macrophage activation. Mechanistic studies showed that S1PR4 was strongly connected to bioactive oxylipins concurrent with bounding to formyl peptide receptor 2 to influence the phosphorylation of JNK and contributed to the macrophage M1 program, which in turn secreted amounts of inflammatory cytokines associated to the inflammatory response of neutrophilic asthma. Furthermore, treating mice with S1PR4 agonist CYM50308 was characterized by less pulmonary inflammatory infiltration. Our research indicates S1PR4 a promising therapeutic target for non-eosinophilic phenotypes of asthma.

Memantine nitrate MN-08 suppresses NLRP3 inflammasome activation to protect against sepsis-induced acute lung injury in mice

Sepsis is a life-threatening organ dysfunction with devastating consequences, prominent among which is lung damage. Memantine, an N-methyl-D-aspartic acid receptor (NMDAR) antagonist, is able to alleviate acute lung injury (ALI). Nitric oxide (NO) suppresses NLRP3 inflammasome activation against lipopolysaccharide (LPS)-induced septic shock. MN-08, a novel nitrate derivative of memantine, possesses both the ability to antagonize NMDAR and release NO. In the present study, we aimed to investigate the protective effects of MN-08 against LPS-induced systemic inflammation and septic lung injury in mice, and to explore the underlying mechanisms of MN-08 in LPS-induced mice and THP-1 macrophages. MN-08 significantly increased the survival rate of septic mice, alleviated LPS-induced sepsis in mice via improving systemic inflammatory response syndrome and immune dysfunction, and attenuated pulmonary injury and inflammatory infiltration. More importantly, the therapeutic benefit of MN-08 for sepsis was greater than that of memantine and dexamethasone. Mechanistically, MN-08 exerted anti-inflammatory activity through inhibiting nuclear translocation of NF-κB, activation of the MAPK signaling pathway and the signaling transduction of STAT3/NF-κB. In addition, MN-08 suppressed NLRP3 inflammasome activation. Taken together, our studies demonstrate that MN-08 may be a promising therapeutic agent for sepsis-induced acute lung injury.

Pulmonary hypertension due to HFpEF in rats

Heart failure with preserved ejection fraction (HFpEF) is frequently complicated by pulmonary hypertension (PH), which underlying mechanism remains largely unknown. When present, it is associated with a worse outcome and there are no therapeutic options for PH due to HFpEF. In this context, we sought to characterize the pulmonary circulation in an experimental model of HFpEF in rats, replicating the characteristics of HFpEF observed in patients. Obesity-prone (OP) and -resistant Sprague-Dawley rats were respectively fed with a high-fat diet or a standard rat chow for 12 months ( n = 10 rats in each group) and evaluated by echocardiography, left (LV) and right ventricular (RV) catheterization, histological and pulmonary artery vasoactive analyses. In OP rats fed with high-fat diet during 12 months, HFpEF was confirmed with preserved LV ejection fraction, LV diastolic dysfunction (assessed by increased LV end-diastolic pressure) associated to concentric LV hypertrophy and fibrosis. In rats with HFpEF, RV systolic pressure was increased (31.6 ± 1.0 versus 26.3 ± 0.5 mmHg, P < 0.001), with no significant changes in pulmonary artery muscularization and inflammatory infiltration. Echocardiography showed an increase in pulmonary artery (PA) diameter and PA-to-aorta diameter ratio associated with an increased RV/LV ratio. Circulating levels of sST2 were increased in rats with HFpEF, while NT-proBNP levels decreased. Ex vivo pulmonary artery contraction to phenylephrine and endothelin-1 was similar in both groups of rats. Our model shows that rats develop HFpEF associated to typical risk factors and present with PH. However, at this early stage of HFpEF, neither pronounced pulmonary structural changes nor RV functional and structural changes were observed, suggesting that other mechanisms are likely involved in the development of pulmonary vascular disease in HFpEF.

NOVEL NANO THERAPEUTIC MATERIALS FOR THE EFFECTIVE TREATMENT OF RHEUMATOID ARTHRITIS-RECENT INSIGHTS

Recent advances in science and technology and greatly modified the way we stumble on, deal with and prevent special diseases in all components of human lifestyles. Rheumatoid arthritis (RA) is the most not unusual complex multifactorial joint related autoimmune, chronic, severe systemic inflammatory ailment with unknown etiology completed with increased cardiovascular risks. It is regularly associated with critical synovial joint inflammation, autoantibody production, cartilage/bone tissue destruction, cardiovascular, pulmonary, skeletal disorders and massive inflammatory infiltration which might in the end motive extreme disability, huge complications, premature mortality and decreased life quality. Pro-inflammatory cytokines like IL-1, IL-6, IL-8 and IL-10 were dependable for the induction of inflammation in RA patients. It has a global occurrence of around 1% with the incidence among women being 2-3 times extra in men. Preclinical RA, genetic variables, and environmental factors have all been linked to the disease's etiology. Because there is no known cure for RA, the primary goal of treatment is to achieve the shortest possible illness duration and, if possible, rehabilitation. Current clinical remedies of RA display numerous drawbacks which include excessive doses, common administration, speedy metabolism, bad absorption, low responsiveness, higher cost and serious side consequences. These obstacles have inspired extremely good growth of the studies and to enhance those obstacles, nanoparticles that are able to encapsulating and protecting tablets from degradation earlier than they reach the target site in vivo, might also function drug delivery structures. Bioavailability and therapeutic bioactivity can be improved, and limited emphasis on damaged joints can be allowed. The current study provides a platform for different lipid nanoparticle methods for RA therapy, using the newly developing field of lipid nanoparticles to improve a targeted theranostic device for RA treatment. This review aims to present the most recent major application of lipid nanoparticles as a biocompatible and biodegradable transport device for improving RA concentration on over free drugs by presenting tissue-specific concentrated on of ligand-controlled drug release by modulating nanoparticle composition. Additionally, we also discuss the pivotal demanding situations to be addressed, as well as destiny views. Therefore, it is feasible to claim that nanoparticles will, within the near future, play a critical role in advanced treatment and affected person-particular cures for human diseases which include RA.

Effects of Elemental Mercury Vapor Inhalation on Arterial Blood Gases, Lung Histology, and Interleukin-1 Expression in Pulmonary Tissues of Rats.

We investigated the effects of elemental mercury vapor inhalation on arterial blood gases (ABGs), lung histology, and interleukin-1 (IL-1) expression in pulmonary tissues in rats. A total of 42 Sprague Dawley rats were divided randomly into three groups. Rats in the first group were used as the control (CG). A short-term group (STG) and a long-term group (LTG) were exposed to 500 μg/m3 of mercury vapor 2 hrs/day for 21 days and 65 days, respectively. After exposure periods were completed, arterial blood samples were obtained, and ABGs were measured. Lung tissue sections were prepared for histology evaluation and immune-stained to detect IL-1 expression. There was a significant decrease in body weight in both STG (15%) and LTG (22%) compared with the CG. In the LTG, six out of 14 (43%) rats died, including two males and four females, while none of the rats in the STG died during the experiment. In both STG and LTG, a significant acid-base imbalance was characterized by a significant decrease in blood pH values and a significant increase in PCO2 values. Both PO2 and SpO2 blood values were significantly decreased in the STG and LTG, while no changes were observed in HCO3 values in all groups. Histological evaluation of lung tissues revealed severe lesions characterized by pulmonary emphysema and inflammatory cellular infiltrate. IL-1 expression in lung tissues was not significantly different between exposed rats and control subjects. These results indicate significant alterations in blood acid-base status characterized by severe respiratory acidosis with hypoxemia and no evidence of compensatory alkalosis in rats after exposure to short- and long-term elementary mercury vapor.

Effects of over-expressing heat shock protein 60 on marrow mesenchymal stem cells in the treatment of phosgene-induced acute lung injury

Objective: To investigate the effect of heat shock protein 60 (HSP60) overexpression on the ability of bone marrow mesenchymal stem cells (MSCs) and its therapeutic effect on rats with phosgene induced acute lung injury. Methods: HSP60 was transfected into MSCs by adenovirus. Western blot was used to measure the expressions of HSP60 before and after transfection. CCK-8 assay was used to detect the activity of MSCs, flow cytometry was used to detect the apoptotic ability of MSCs, and Transwell assay was used to observe the migration ability of MSCs. Sixty SPF grade male SD rats were randomly divided into control group, phosgene exposure group (inhalation of phosgene for 5 min) , MSCs group (phosgene exposure, MSCs treatment group) and transfected MSCs group (phosgene exposure, overexpression of HSP60 MSCs treatment group) . The pathological changes of lung were observed by lung pathological section, lung wet dry ratio, the degree of pulmonary edema, the total cell count and total protein content of alveolar lavage fluid, the inflammatory changes of tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6) in BALF and serum were observed. The data were analyzed by Graphpad Prism 8.0 software. Paired comparisons were performed by non paired t-test. One way ANOVA was used for comparison between groups. Results: The proliferation ability of MSCs transfected with HSP60[A= (0.69±0.05) ] was significantly higher than that of MSCs not transfected with HSP60[A= (0.27±0.02) ] (P<0.05) . Compared with the phosgene exposure group, the pulmonary edema and inflammatory factor infiltration of MSCs group and MSCs transfected group were reduced. However, compared with MSCs group, the degree of pulmonary edema in MSCs transfected group was significantly improved, the levels of inflammatory factors IL-6 and TNF-α were significantly decreased, and the total protein content and total cell count in bronchoalveolar lavage fluid were less (P<0.05) . Conclusion: MSCs transfected with HSP60 can enhance the ability of proliferation, anti apoptosis, migration and the curative effect in rats with phosgene induced acute lung injury.

Exposure to O3 during pregnancy and offspring asthma induced by OVA: Sensitive window identification.

Evidence proved that gestational ozone (O3) exposure can increase the risk of neonatal adverse respiratory outcomes, but offspring asthma is unclear. This study aimed to investigate whether gestational O3 exposure could exacerbate offspring asthma, and to research the differences in effects of O3 exposure at different gestational periods on offspring asthma. The pregnant ICR mice were randomly grouped and were administered O3 (air as control) at gestational day (GD) 1-6, 7-12, and 13-18, respectively. The pups aged 2-4 weeks were treated with ovalbumin (OVA) to establish a model of early life asthma. Asthma characteristics such as pulmonary inflammation, goblet cell proliferation, airway remodeling, OVA-specific immunoglobulin (Ig) E secretion and cytokines were examined. OVA sensitization and challenge successfully induced asthma in offspring. Compared with the air control, pulmonary inflammation infiltration, mucous secretion, the concentration of OVA-specific IgE, the level of tumor necrosis factor (TNF)-α, and T helper (Th) 2-skewed response were significantly exacerbated when O3 exposure at GD13-18 following inhaling OVA, while pulmonary inflammatory infiltration, mucus secretion, and Th2-skewed response were not significantly changed when O3 exposure at both GD1-6 and GD7-12. What's more, the above indicators in asthmatic offspring due to O3 exposure at GD13-18 were more severe than at GD1-6 and GD7-12. Interestingly, the signs of asthma only appeared in the offspring after OVA inhalation. When offspring were not treated with OVA, the prenatal O3 exposure alone did not lead to asthmatic reactions in offspring. In addition, O3 exposure at GD13-18 markedly increased the number of neutrophils and macrophages in Bronchoalveolar Lavage Fluid (BALF) of asthmatic offspring, and significantly exacerbated Th2 immune imbalance in asthmatic offspring, but had no effect on Th17 immune imbalance. Exposure to O3 during pregnancy aggravated asthma in offspring, in which the third trimester is the most sensitive window.

Connexin-43 is a promising target for pulmonary hypertension due to hypoxaemic lung disease.

The mechanisms underlying pulmonary hypertension (PH) are complex and multifactorial, and involve different cell types that are interconnected through gap junctional channels. Although connexin (Cx)-43 is the most abundant gap junction protein in the heart and lungs, and critically governs intercellular signalling communication, its contribution to PH remains unknown. The focus of the present study is thus to evaluate Cx43 as a potential new target in PH.Expressions of Cx37, Cx40 and Cx43 were studied in lung specimens from patients with idiopathic pulmonary arterial hypertension (IPAH) or PH associated with chronic hypoxaemic lung diseases (chronic hypoxia-induced pulmonary hypertension (CH-PH)). Heterozygous Cx43 knockdown CD1 (Cx43+/-) and wild-type littermate (Cx43+/+) mice at 12 weeks of age were randomly divided into two groups, one of which was maintained in room air and the other exposed to hypoxia (10% oxygen) for 3 weeks. We evaluated pulmonary haemodynamics, remodelling processes in cardiac tissues and pulmonary arteries (PAs), lung inflammation and PA vasoreactivity.Cx43 levels were increased in PAs from CH-PH patients and decreased in PAs from IPAH patients; however, no difference in Cx37 or Cx40 levels was noted. Upon hypoxia treatment, the Cx43+/- mice were partially protected against CH-PH when compared to Cx43+/+ mice, with reduced pulmonary arterial muscularisation and inflammatory infiltration. Interestingly, the adaptive changes in cardiac remodelling in Cx43+/- mice were not affected. PA contraction due to endothelin-1 (ET-1) was increased in Cx43+/- mice under normoxic and hypoxic conditions.Taken together, these results indicate that targeting Cx43 may have beneficial therapeutic effects in PH without affecting compensatory cardiac hypertrophy.

Resveratrol Attenuates Allergic Asthma and Associated Inflammation in the Lungs Through Regulation of miRNA-34a That Targets FoxP3 in Mice.

Asthma is a chronic inflammatory disease of airways mediated by T-helper 2 (Th2) cells involving complex signaling pathways. Although resveratrol has previously been shown to attenuate allergic asthma, the role of miRNA in this process has not been studied. We investigated the effect of resveratrol on ovalbumin-induced experimental allergic asthma in mice. To that end, BALB/c mice were immunized with ovalbumin (OVA) intraperitoneally followed by oral gavage of vehicle (OVA-veh) or resveratrol (100 mg/kg body) (OVA-res). On day 7, the experimental groups received intranasal challenge of OVA followed by 7 days of additional oral gavage of vehicle or resveratrol. At day 15, all mice were euthanized and bronchioalveolar fluid (BALF), serum and lung infiltrating cells were collected and analyzed. The data showed that resveratrol significantly reduced IL-5, IL-13, and TGF-β in the serum and BALF in mice with OVA-induced asthma. Also, we saw a decrease in CD3+CD4+, CD3+CD8+, and CD4+IL-4+ cells with increase in CD4+CD25+FOXP3+ cells in pulmonary inflammatory cell infiltrate in OVA-res group when compared to OVA-veh. miRNA expression arrays using lung infiltrating cells showed that resveratrol caused significant alterations in miRNA expression, specifically downregulating the expression of miR-34a. Additionally, miR-34a was found to target FOXP3, as evidenced by enhanced expression of FOXP3 in the lung tissue. Also, transfection studies showed that miR-34a inhibitor upregulated FOXP3 expression while miR-34a-mimic downregulated FOXP3 expression. The current study suggests that resveratrol attenuates allergic asthma by downregulating miR-34a that induces increased expression of FOXP3, a master regulator of Treg development and functions.