Crystalline silica-induced pulmonary inflammation and autoimmunity in mature adult NZBW/f1 mice: age-related sensitivity and impact of omega-3 fatty acid intervention.

OBJECTIVE: Occupational exposure to respirable crystalline silica (cSiO2) has been linked to lupus development. Previous studies in young lupus-prone mice revealed that intranasal cSiO2 exposure triggered autoimmunity, preventable with docosahexaenoic acid (DHA). This study explores cSiO2 and DHA effects in mature lupus-prone adult mice, more representative of cSiO2-exposed worker age. METHODS: Female NZBWF1 mice (14-week old) were fed control (CON) or DHA-supplemented diets. After two weeks, mice were intranasally instilled saline (VEH) or 1 mg cSiO2 weekly for four weeks. Cohorts were then analyzed 1- and 5-weeks postinstillation for lung inflammation, cell counts, chemokines, histopathology, B- and T-cell infiltration, autoantibodies, and gene signatures, with results correlated to autoimmune glomerulonephritis onset. RESULTS: VEH/CON mice showed no pathology. cSiO2/CON mice displayed significant ectopic lymphoid tissue formation in lungs at 1 week, increasing by 5 weeks. cSiO2/CON lungs exhibited elevated cellularity, chemokines, CD3+ T-cells, CD45R + B-cells, IgG + plasma cells, gene expression, IgG autoantibodies, and glomerular hypertrophy. DHA supplementation mitigated all these effects. DISCUSSION: The mature adult NZBWF1 mouse used here represents a life-stage coincident with immunological tolerance breach and one that more appropriately represents the age (20-30 yr) of cSiO2-exposed workers. cSiO2-induced robust pulmonary inflammation, autoantibody responses, and glomerulonephritis in mature adult mice, surpassing effects observed previously in young adults. DHA at a human-equivalent dosage effectively countered cSiO2-induced inflammation/autoimmunity in mature mice, mirroring protective effects in young mice. CONCLUSION: These results highlight life-stage significance in this preclinical lupus model and underscore omega-3 fatty acids' therapeutic potential against toxicant-triggered autoimmune responses.

Rice Bran Oil Improves Emphysema in Cigarette Smoke Extract-Induced Mice through Anti-Inflammatory and Antioxidative Effects.

Lung inflammation and alveolar enlargement are the major pathological conditions of chronic obstructive pulmonary disease (COPD) patients. Rice bran oil (RBO), a natural anti-inflammatory and antioxidative agent, has been used for therapeutic purposes in several inflammatory diseases. This study aimed to investigate the anti-inflammatory and antioxidative effect of RBO on a cigarette smoke extract (CSE)-induced emphysema model in mice. The results indicated that CSE significantly induced airspace enlargement in mouse lung. Increased inflammatory cells, macrophage, and TNF-alpha levels in bronchoalveolar lavage fluid (BALF) were noticed in CSE-treated mice. RBO (low and high dose)-supplemented mice showed decreased total BALF inflammatory cell, macrophage, and neutrophil numbers and TNF-alpha levels (p < 0.05). Additionally, the administration of RBO decreased the mean linear alveolar intercept (MLI) in the CSE-treated group. Additionally, RBO treatment significantly increased the total antioxidant capacity in both mouse BALF and serum. However, RBO did not have an effect on the malondialdehyde (MDA) level. These findings suggested that RBO treatment ameliorates lung inflammation in a CSE-induced emphysema mice model through anti-inflammatory and antioxidant pathways. Therefore, the supplementation of RBO could be a new potential therapeutic to relieve the severity of COPD.

Qingfei Tongluo Mixture Attenuates Bleomycin-Induced Pulmonary Inflammation and Fibrosis through mTOR-Dependent Autophagy in Rats.

As an interstitial fibrosis disease characterized by diffuse alveolitis and structural alveolar disorders, idiopathic pulmonary fibrosis (IPF) has high lethality but lacks limited therapeutic drugs. A hospital preparation used for the treatment of viral pneumonia, Qingfei Tongluo mixture (QFTL), is rumored to have protective effects against inflammatory and respiratory disease. This study aims to confirm whether it has a therapeutic effect on bleomycin-induced IPF in rats and to elucidate its mechanism of action. Male SD rats were randomly divided into the following groups: control, model, CQ + QFTL (84 mg/kg chloroquine (CQ) + 3.64 g/kg QFTL), QFTL-L, M, H (3.64, 7.28, and 14.56 g/kg, respectively) and pirfenidone (PFD 420 mg/kg). After induction modeling and drug intervention, blood samples and lung tissue were collected for further detection. Body weight and lung coefficient were examined, combined with hematoxylin and eosin (H&E) and Masson staining to observe lung tissue lesions. The enzyme-linked immunosorbent assay (ELISA) and the hydroxyproline (HYP) assay kit were used to detect changes in proinflammatory factors (transforming growth factor-ß (TGF-ß), tumor necrosis factor-α (TNF-α), and interleukin-1ß (IL-1ß)) and HYP. Immunohistochemistry and Western blotting were performed to observe changes in proteins related to pulmonary fibrosis (α-smooth muscle actin (α-SMA) and matrix metalloproteinase 12 (MMP12)) and autophagy (P62 and mechanistic target of rapamycin (mTOR)). Treatment with QFTL significantly improved the adverse effects of bleomycin on body weight, lung coefficient, and pathological changes. Then, QFTL reduced bleomycin-induced increases in proinflammatory mediators and HYP. The expression changes of pulmonary fibrosis and autophagy marker proteins are attenuated by QFTL. Furthermore, the autophagy inhibitor CQ significantly reversed the downward trend in HYP levels and α-SMA protein expression, which QFTL improved in BLM-induced pulmonary fibrosis rats. In conclusion, QFTL could effectively attenuate bleomycin-induced inflammation and pulmonary fibrosis through mTOR-dependent autophagy in rats. Therefore, QFTL has the potential to be an alternative treatment for IPF in clinical practice.

Anti-Acinetobacter Baumannii single-chain variable fragments provide therapeutic efficacy in an immunocompromised mouse pneumonia model.

BACKGROUND: The emergence of carbapenem-resistant and extensively drug-resistant (XDR) Acinetobacter baumannii as well as inadequate effective antibiotics calls for an urgent effort to find new antibacterial agents. The therapeutic efficacy of two human scFvs, EB211 and EB279, showing growth inhibitory activity against A. baumannii in vitro, was investigated in immunocompromised mice with A. baumannii pneumonia. RESULTS: The data revealed that infected mice treated with EB211, EB279, and a combination of the two scFvs showed better survival, reduced bacterial load in the lungs, and no marked pathological abnormalities in the kidneys, liver, and lungs when compared to the control groups receiving normal saline or an irrelevant scFv. CONCLUSIONS: The results from this study suggest that the scFvs with direct growth inhibitory activity could offer promising results in the treatment of pneumonia caused by XDR A. baumannii.

Corticosteroid-resistant immune-related adverse events: a systematic review.

Immune checkpoint inhibitor (ICI) treatment has become an important therapeutic option for various cancer types. Although the treatment is effective, ICI can overstimulate the patient's immune system, leading to potentially severe immune-related adverse events (irAEs), including hepatitis, colitis, pneumonitis and myocarditis. The initial mainstay of treatments includes the administration of corticosteroids. There is little evidence how to treat steroid-resistant (sr) irAEs. It is mainly based on small case series or single case reports. This systematic review summarizes available evidence about sr-irAEs. We conducted a systematic literature search in PubMed. Additionally, we included European Society for Medical Oncology, Society for Immunotherapy of Cancer, National Comprehensive Cancer Network and American Society of Clinical Oncology Guidelines for irAEs in our assessment. The study population of all selected publications had to include patients with cancer who developed hepatitis, colitis, pneumonitis or myocarditis during or after an immunotherapy treatment and for whom corticosteroid therapy was not sufficient. Our literature search was not restricted to any specific cancer diagnosis. Case reports were also included. There is limited data regarding life-threatening sr-irAEs of colon/liver/lung/heart and the majority of publications are single case reports. Most publications investigated sr colitis (n=26), followed by hepatitis (n=21), pneumonitis (n=17) and myocarditis (n=15). There is most data for mycophenolate mofetil (MMF) to treat sr hepatitis and for infliximab, followed by vedolizumab, to treat sr colitis. Regarding sr pneumonitis there is most data for MMF and intravenous immunoglobulins (IVIG) while data regarding infliximab are conflicting. In sr myocarditis, most evidence is available for the use of abatacept or anti-thymocyte globulin (ATG) (both with or without MMF) or ruxolitinib with abatacept. This review highlights the need for prompt recognition and treatment of sr hepatitis, colitis, pneumonitis and myocarditis. Guideline recommendations for sr situations are not defined precisely. Based on our search, we recommend-as first line treatment-(1) MMF for sr hepatitis, (2) infliximab for sr colitis, followed by vedolizumab, (3) MMF and IVIG for sr pneumonitis and (4) abatacept or ATG (both with or without MMF) or ruxolitinib with abatacept for sr myocarditis. These additional immunosuppressive agents should be initiated promptly if there is no sufficient response to corticosteroids within 3 days.

Liquefied Petroleum Gas or Biomass Cooking and Severe Infant Pneumonia.

BACKGROUND: Exposure to household air pollution is a risk factor for severe pneumonia. The effect of replacing biomass cookstoves with liquefied petroleum gas (LPG) cookstoves on the incidence of severe infant pneumonia is uncertain. METHODS: We conducted a randomized, controlled trial involving pregnant women 18 to 34 years of age and between 9 to less than 20 weeks' gestation in India, Guatemala, Peru, and Rwanda from May 2018 through September 2021. The women were assigned to cook with unvented LPG stoves and fuel (intervention group) or to continue cooking with biomass fuel (control group). In each trial group, we monitored adherence to the use of the assigned cookstove and measured 24-hour personal exposure to fine particulate matter (particles with an aerodynamic diameter of ≤2.5 µm [PM2.5]) in the women and their offspring. The trial had four primary outcomes; the primary outcome for which data are presented in the current report was severe pneumonia in the first year of life, as identified through facility surveillance or on verbal autopsy. RESULTS: Among 3200 pregnant women who had undergone randomization, 3195 remained eligible and gave birth to 3061 infants (1536 in the intervention group and 1525 in the control group). High uptake of the intervention led to a reduction in personal exposure to PM2.5 among the children, with a median exposure of 24.2 µg per cubic meter (interquartile range, 17.8 to 36.4) in the intervention group and 66.0 µg per cubic meter (interquartile range, 35.2 to 132.0) in the control group. A total of 175 episodes of severe pneumonia were identified during the first year of life, with an incidence of 5.67 cases per 100 child-years (95% confidence interval [CI], 4.55 to 7.07) in the intervention group and 6.06 cases per 100 child-years (95% CI, 4.81 to 7.62) in the control group (incidence rate ratio, 0.96; 98.75% CI, 0.64 to 1.44; P = 0.81). No severe adverse events were reported to be associated with the intervention, as determined by the trial investigators. CONCLUSIONS: The incidence of severe pneumonia among infants did not differ significantly between those whose mothers were assigned to cook with LPG stoves and fuel and those whose mothers were assigned to continue cooking with biomass stoves. (Funded by the National Institutes of Health and the Bill and Melinda Gates Foundation; HAPIN ClinicalTrials.gov number, NCT02944682.).

Quercetin alleviates PM2.5-induced chronic lung injury in mice by targeting ferroptosis.

Background: PM2.5 is a well-known harmful air pollutant that can lead to acute exacerbation and aggravation of respiratory diseases. Although ferroptosis is involves in the pathological process of pulmonary disease, the potential mechanism of ferroptosis in PM2.5-caused lung inflammation and fibrosis need to be further clarified. Quercetin is a phenolic compound that can inhibit ferroptosis in various diseases. Hence, this study explores the role of ferroptosis in lung injury induced by PM2.5 in order to further elucidate the beneficial effect of quercetin and its underlying mechanism. Methods: C57BL/6J mice were treated with either saline or PM2.5 by intratracheal instillation 20 times (once every two days). Additionally, PM2.5-treated mice were supplemented with two doses of quercetin. Lung injury, lipid peroxidation, iron content and ferroptosis marker protein expression and the Nrf2 signaling pathway were evaluated. In vitro, cell experiments were applied to verify the mechanisms underlying the links between Nrf2 signaling pathway activation and ferroptosis as well as between ferroptosis and inflammation. Results: In vivo, PM2.5 increased lung inflammation and caused lung fibrosis and increased lipid peroxidation contents, iron contents and ferroptosis markers in lung tissues; these effects were significantly reversed by quercetin. Additionally, quercetin upregulated the nuclear Nrf2 expression and downregulated Keap1 expression in lung tissues of PM2.5-exposed mice. Quercetin decreased lipid peroxidation products, iron contents and ferroptosis levels and increased the nuclear translocation of Nrf2 and the degradation of Keap1 in PM2.5-exposed BEAS-2B cells. Moreover, we found that quercetin and dimethyl fumarate markedly decreased lipid peroxidation production and ferroptosis by activating the Nrf2-Keap1 pathway in PM2.5-exposed cells. Furthermore, quercetin reduced inflammatory cytokines and TGF-ß1 in PM2.5-exposed cells. Conclusion: Our data suggested that Nrf2 is involved in ferroptosis in PM2.5-induced lung injury, and quercetin can alleviate these adverse effects via activating Nrf2-Keap1 signaling pathway.

Inhibition of Polyinosinic-Polycytidylic Acid-Induced Acute Pulmonary Inflammation and NF-κB Activation in Mice by a Banana Plant Extract.

NF-κB activation is pivotal for the excess inflammation causing the critical condition and mortality of respiratory viral infection patients. This study was aimed to evaluate the effect of a banana plant extract (BPE) on suppressing NF-κB activity and acute lung inflammatory responses in mice induced by a synthetic double-stranded RNA viral mimetic, polyinosinic-polycytidylic acid (poly (I:C)). The inflammatory responses were analyzed by immunohistochemistry and HE stains and ELISA. The NF-κB activities were detected by immunohistochemistry in vivo and immunofluorescence and Western blot in vitro. Results showed that BPE significantly decreased influx of immune cells (neutrophils, lymphocytes, and total WBC), markedly suppressed the elevation of pro-inflammatory cytokines and chemokines (IL-6, RANTES, IFN-γ, MCP-1, keratinocyte-derived chemokine, and IL-17), and restored the diminished anti-inflammatory IL-10 in the bronchoalveolar lavage fluid (BALF) of poly (I:C)-stimulated mice. Accordingly, HE staining revealed that BPE treatment alleviated poly (I:C)-induced inflammatory cell infiltration and histopathologic changes in mice lungs. Moreover, immunohistochemical analysis showed that BPE reduced the pulmonary IL-6, CD11b (macrophage marker), and nuclear NF-κB p65 staining intensities, whilst restored that of IL-10 in poly (I:C)-stimulated mice. In vitro, BPE antagonized poly(I:C)-induced elevation of IL-6, nitric oxide, reactive oxygen species, NF-κB p65 signaling, and transient activation of p38 MAPK in human lung epithelial-like A549 cells. Taken together, BPE ameliorated viral mimic poly(I:C)-induced acute pulmonary inflammation in mice, evidenced by reduced inflammatory cell infiltration and regulation of both pro- and anti-inflammatory cytokines. The mechanism of action might closely associate with NF-κB signaling inhibition.

Clinical evaluation of targeted sedation nursing combined with comprehensive nursing in children with severe pneumonia.

The severity of severe pneumonia in children depends on the degree of local inflammation, spread of lung inflammation and systemic inflammatory response. Appropriate care can effectively reduce the mortality of children with severe pneumonia. This study was designed to explore the nursing effect of targeted sedation nursing and comprehensive nursing intervention in children with severe pneumonia. Eighty children with severe pneumonia who complained of the main complaint were selected, and they were evenly distributed to receive comprehensive care (control group) and targeted sedation care and comprehensive care (observation group). In each group, different degrees of sedation, pain scores, and changes in adverse reactions were evaluated. Before nursing, the sedation and pain scores of the 2 groups of children were not statistically significant; after nursing, the sedation and pain scores of the 2 groups of children improved with time, and the sedation effect of the observation group was significantly lower than that of the control. In the group, the pain score was lower than that of the control group, indicating improvement. The SAS and SDS of the observation group were lower than those of the control group, while the social support score was significantly higher than that of the control group. The difference was statistically significant (P < .05). The accidental extubation, delirium, respiratory depression, and laryngospasm of the 2 groups of children were significantly improved, and the observation group was significantly less than the control group. This difference was statistically significant (P < .05). Targeted sedation nursing and comprehensive nursing intervention can effectively reduce the incidence of adverse reactions in children with severe pneumonia, reduce the pain and discomfort of children with severe pneumonia, and significantly improve the degree of sedation, which has certain reference value for the care of children with severe pneumonia.

Insights into the preventive actions of natural compounds against Klebsiella pneumoniae infections and drug resistance.

Klebsiella pneumoniae is a type of Gram-negative bacteria that causes a variety of infections, including pneumonia, bloodstream infections, wound infections, and meningitis. The treatment of K. pneumoniae infection depends on the type of infection and the severity of the symptoms. Antibiotics are generally used to treat K. pneumoniae infections. However, some strains of K. pneumoniae have become resistant to antibiotics. This comprehensive review examines the potential of natural compounds as effective strategies against K. pneumonia infections. The alarming rise in antibiotic resistance underscores the urgent need for alternative therapies. This article represents current research on the effects of diverse natural compounds, highlighting their anti-microbial and antibiofilm properties against K. pneumonia. Notably, compounds such as andrographolide, artemisinin, baicalin, berberine, curcumin, epigallocatechin gallate, eugenol, mangiferin, piperine, quercetin, resveratrol, and thymol have been extensively investigated. These compounds exhibit multifaceted mechanisms, including disruption of bacterial biofilms, interference with virulence factors, and augmentation of antibiotic effectiveness. Mechanistic insights into their actions include membrane perturbation, oxidative stress induction, and altered gene expression. While promising, challenges such as limited bioavailability and varied efficacy across bacterial strains are addressed. This review further discusses the potential of natural compounds as better alternatives in combating K. pneumonia infection and emphasizes the need for continued research to harness their full therapeutic potential. As antibiotic resistance persists, these natural compounds offer a promising avenue in the fight against K. pneumonia and other multidrug-resistant pathogens.

Current treatment options for pneumonia caused by carbapenem-resistant Acinetobacter baumannii.

PURPOSE OF REVIEW: The purpose of this review is to briefly summarize the challenges associated with the treatment of pneumonia caused by carbapenem-resistant Acinetobacter baumannii (CRAB), discuss its carbapenem-resistance, and review the literature supporting the current treatment paradigm and therapeutic options. RECENT FINDINGS: In a multicenter, randomized, and controlled trial the novel ß-lactam-ß-lactamase inhibitor sulbactam-durlobactam was compared to colistin, both in addition to imipenem-cilastatin. The drug met the prespecified criteria for noninferiority for 28-day all-cause mortality while demonstrating higher clinical cure rates in the treatment of CRAB pneumonia. In an international, randomized, double-blind, placebo controlled trial colistin monotherapy was compared to colistin combined with meropenem. In this trial, combination therapy was not superior to monotherapy in the treatment of drug-resistant gram-negative organisms including CRAB pneumonia. SUMMARY: CRAB pneumonia is a preeminent public health threat without an agreed upon first line treatment strategy. Historically, there have been drawbacks to available treatment modalities without a clear consensus on the first-line treatment regimen. CRAB pneumonia is a top priority for the continued development of antimicrobials, adjuvant therapies and refinement of current treatment strategies.

Elucidating the anti-inflammatory activity of platycodins in lung inflammation through pulmonary distribution dynamics and grey relational analysis of cytokines.

ETHNOPHARMACOLOGICAL RELEVANCE: Platycodonis Radix (PR) is a traditional herbal remedy used to prevent and treat lung inflammation, and platycodins are speculated to be the major active constituents. However, concrete experimental verification for this assertion remains absent thus far. AIM OF THE STUDY: This study aims to compare the pulmonary distribution dynamics of five platycodins and analyze their effects on cytokines. Through the grey relational analysis (GRA) between pulmonary active components and cytokines, the study ascertains platycodins as the potential effective component against lung inflammation. MATERIALS AND METHODS: A rat lung inflammation model was created using lipopolysaccharides (LPS). Pulmonary distribution dynamics were analyzed via LC-MS/MS. Cytokine changes and distribution patterns in lung tissues were studied by multi-factor reagent kit. GRA was applied to determine correlations between pulmonary components and cytokines. Finally, the anti-inflammatory properties of platycodins were further studied using LPS-induced BEAS-2B cells in vitro. RESULTS: The results showed that five platycodins (Platycodin D, Platycodin D3, Deapio Platycodin D, 3-O-ß-D-Glucopyranosyl Platycodigenin, and Platycodigenin) featured fast absorption rate, short time to peak, and slow metabolism rate. The pulmonary distribution dynamics were significantly affected within 2 h after LPS modeling. At the same time, PR altered the relationships among different cytokines induced by LPS stimulation, particularly inflammatory cytokines IL-6 and IFN-γ. The GRA results indicated good correlation between the pulmonary distribution dynamics of the five platycodins components and the changing patterns of cytokine levels, with Platycodin D3 contributing the most. Additionally, Platycodin D3 exhibited a protective role against LPS-induced inflammation by reducing the production of pro-inflammatory mediators such as IL-1ß, IL-8, and ROS, as well as increasing the expression of the anti-inflammatory mediator IL-10. CONCLUSIONS: Platycodins are the main anti-inflammatory agents in PR and there is a good correlation with cytokines. This contributes to the anti-pneumonia effect of PR.

Vitamin D and Respiratory Diseases : Based on 11th Dr. I. C. Verma Excellence in Research Award for Young Pediatricians Delivered as Oration on 15th Oct. 2023.

The significance of Vitamin D has been appreciated beyond bone health and calcium metabolism. The importance of Vitamin D in respiratory health has been recognized due to its immunomodulatory and anti-microbial properties. The hypothesis is that Vitamin D could have a significant role in the pathogenesis of respiratory diseases and may represent a novel preventive and therapeutic strategy. Furthermore, enumerable observational studies established the association of Vitamin D deficiency with respiratory diseases such as asthma, bronchiolitis, pneumonia, tuberculosis, etc. However, experimental studies have not shown the encouraging results. This brief review will summarize and discuss the synthesis and metabolism of Vitamin D, the prevalence of Vitamin D deficiency in children, its role in the pathogenesis of various childhood respiratory diseases, and an overview of the therapeutic trials assessing the role of Vitamin D supplementation in childhood respiratory diseases.

Perillaldehyde: A promising antibacterial agent for the treatment of pneumonia caused by Acinetobacter baumannii infection.

Perillaldehyde is a monoterpene compound mainly from the medicinal plant Perilla frutescens (L.) Britt., which has hypolipidemic, antioxidant, antibacterial and anti-inflammatory functions. In this investigation, we discovered that Perillaldehyde had powerful antimicrobial activity against Acinetobacter baumannii 5F1, and its minimum inhibitory concentration was 287.08 µg/mL. A. baumannii is a conditionally pathogenic bacterium with a high clinical resistance rate and is a major source of hospital infections, especially in intensive care units, which is one of the main causes of pneumonia. Inflammatory immune response is characteristic of pneumonia caused by A. baumannii infection. The results of our in vitro experiments indicate that Perillaldehyde disrupts the cell membrane of A. baumannii 5F1 and inhibits its quorum sensing to inhibit biofilm formation, among other effects. With an experimental model of murine pneumonia, we investigated that Perillaldehyde decreased NLRP3 inflammasome activation and TNF-α expression in lung tissues by inhibiting the NF-κB pathway, and also impacted MAPKs protein signaling pathway through the activation of TLR4. Notably, the use of high doses of Perillaldehyde for the treatment of pneumonia caused by A. baumannii 5F1 infection resulted in a survival rate of up to 80 % in mice. In summary, we demonstrated that Perillaldehyde is promising as a new drug for the treatment of pneumonia caused by A. baumannii 5F1 infection.

Modified Bushen Yiqi Formula mitigates pulmonary inflammation and airway remodeling by inhibiting neutrophils chemotaxis and IL17 signaling pathway in rats with COPD.

ETHNOPHARMACOLOGICAL RELEVANCE: Chronic obstructive pulmonary disease (COPD) is a major global health concern characterized by pulmonary inflammation and airway remodeling. Traditional Chinese medicine, such as Modified Jiawei Bushen Yiqi Formula (MBYF), has been used as a complementary therapy for COPD in China. AIM OF THE STUDY: To investigate the therapeutic potential of MBYF in a rat model of COPD induced by cigarette smoke (CS) exposure and explore the underlying mechanism. MATERIALS AND METHODS: The COPD rat model was established through 24 weeks of CS exposure, with MBYF administration starting in the 9th week. Pulmonary function, histological analysis, inflammatory cell count and molecular assays were employed to assess the effects of MBYF on airway remodeling, pulmonary inflammation, neutrophils chemotaxis and the IL17 signaling pathway. RESULTS: MBYF treatment effectively delayed airway remodeling, as evidenced by improved pulmonary function parameters. Histological examination and bronchoalveolar lavage fluid analysis revealed that MBYF mitigated CS-induced pulmonary inflammation by reducing inflammatory cell infiltration. Pharmacological network analysis suggested that MBYF may act through the IL17 signaling pathway to regulate inflammatory responses. RNA-sequencing and molecular assays indicated that MBYF inhibited neutrophils chemotaxis through downregulating the CXCL1/CXCL5/CXCL8-CXCR2 axis, and suppressed IL17A, IL17F and its downstream cytokines, including IL6, TNFα, IL1ß, and COX2. Furthermore, MBYF inhibited the activation of NF-κB and MAPKs in the IL17 signaling pathway. CONCLUSION: MBYF exhibits potential as an adjunct or alternative treatment for COPD, effectively mitigating CS-induced pulmonary inflammation and airway remodeling through the inhibition of neutrophil chemotaxis and IL17 signaling pathway.

Monochasma savatieri Franch. protects against acute lung injury via α7nAChR-TLR4/NF-κB p65 signaling pathway based on integrated pharmacology analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Acute lung injury (ALI) is a life-threatening condition with high morbidity and mortality, underscoring the urgent need for novel treatments. Monochasma savatieri Franch. (LRC) is commonly used clinically to treat wind-heat cold, bronchitis, acute pneumonia and acute gastroenteritis. However, its role in the treatment of ALI and its mechanism of action are still unclear. AIM OF THE STUDY: This study aimed to demonstrate the pharmacological effects and underlying mechanisms of LRC extract, and provide important therapeutic strategies and theoretical basis for ALI. MATERIALS AND METHODS: In this study, a research paradigm of integrated pharmacology combining histopathological analysis, network pharmacology, metabolomics, and biochemical assays was used to elucidate the mechanisms underlaying the effects of LRC extract on LPS-induced ALI in BALB/c mice. RESULTS: The research findings demonstrated that LRC extract significantly alleviated pathological damage in lung tissues and inhibited apoptosis in alveolar epithelial cells, and the main active components were luteolin, isoacteoside, and aucubin. Lung tissue metabolomic and immunohistochemical methods confirmed that LRC extract could restore metabolic disorders in ALI mice by correcting energy metabolism imbalance, activating cholinergic anti-inflammatory pathway (CAP), and inhibiting TLR4/NF-κB signaling pathway. CONCLUSIONS: This study showed that LRC extract inhibited the occurrence and development of ALI inflammation by promoting the synthesis of antioxidant metabolites, balancing energy metabolism, activating CAP and suppressing the α7nAChR-TLR4/NF-κB p65 signaling pathway. In addition, our study provided an innovative research model for exploring the effective ingredients and mechanisms of traditional Chinese medicine. To the best of our knowledge, this is the first report describing the protective effects of LRC extract in LPS-induced ALI mice.

Zinc deficiency increases lung inflammation and fibrosis in obese mice by promoting oxidative stress.

BACKGROUND: Zinc deficiency can lead to multiple organ damage. In this study, we investigated the effects of zinc deficiency on obesity-related lung damage. METHODS: C57BL/6 J mice were fed a diet with differing amounts of zinc and fat over a 6-month period. Palmitic acid was used to stimulate A549 cells to construct a high-fat alveolar epithelial cell model. Western blotting and histopathological staining were performed on animal tissues. Nuclear expression of nuclear factor erythroid 2-related factor 2 (Nrf2) was detected in cultured cells. A reactive oxygen species (ROS) assay kit was used to detect intracellular ROS. Furthermore, Nrf2 siRNA was used to examine zinc deficiency effects on A549 cells. RESULTS: Pathological results showed significant damage to the lung structure of mice in the high-fat and low-zinc diet group, with a significant increase in the expression of inflammatory (IL-6, TNF-α) and fibrosis (TGFß1, PAI-1) factors, combined with a decrease in the expression of Nrf2, HO-1 and NQO1 in the antioxidant pathway. In A549 cells, high fat and low zinc levels aggravated ROS production. Western blot and immunofluorescence results showed that high fat and zinc deficiency inhibited Nrf2 expression. After Nrf2-specific knockout in A549 cells, the protective effect of zinc on oxidant conditions induced by high fat was reduced. Phosphorylated Akt and PI3K levels were downregulated on the high-fat and low-zinc group compared with the high-fat group. CONCLUSIONS: Zinc attenuated lung oxidative damage in obesity-related lung injury and Nrf2 activation is one of the important mechanisms of this effect. GENERAL SIGNIFICANCE: Regulating zinc homeostasis through dietary modifications or supplemental nutritional therapy can contribute to the prevention and treatment of obesity-related lung injury.

Naringin alleviates pneumonia caused by Klebsiella pneumoniae infection by suppressing NLRP3 inflammasome.

Klebsiella pneumoniae (Kpn) is an important pathogen of hospital-acquired pneumonia, which can lead to sepsis and death in severe cases. In this study, we simulated pneumonia induced by Kpn infection in mice to investigate the therapeutic effect of naringin (NAR) on bacterial-induced lung inflammation. Mice infected with Kpn exhibited increases in white blood cells (WBC) and neutrophils in the peripheral blood and pathological severe injury of the lungs. This injury was manifested by increased expression of the inflammatory cytokines interleukin (IL)- 18, IL-1ß, tumor necrosis factor-α (TNF-α) and IL-6, and elevated the expression of NLRP3 protein. NAR treatment could decrease the protein expression of NLRP3, alleviate lung inflammation, and reduce lung injury in mice caused by Kpn. Meanwhile, molecular docking results suggest NAR could bind to NLRP3 and Surface Plasmon Resonance (SPR) analyses also confirm this result. In vitro trials, we found that pretreated with NAR not only inhibited nuclear translocation of nuclear factor (NF)-κB protein P65 but also attenuated the protein interaction of NLRP3, caspase-1 and ASC and inhibited the assembly of NLRP3 inflammasome in mice AMs. Additionally, NAR could reduce intracellular potassium (K+) efflux, inhibiting NLRP3 inflammasome activation. These results indicated that NAR could protect against Kpn-induced pneumonia by inhibiting the overactivation of the NLRP3 inflammasome signaling pathway. The results of this study confirm the efficacy of NAR in treating bacterial pneumonia, refine the mechanism of action of NAR, and provide a theoretical basis for the research and development of NAR as an anti-inflammatory adjuvant.

Modeling longitudinal oral health status and pneumonia risk: secondary data analyses of an integrated dental-medical cohort.

BACKGROUND: Mounting evidence indicates potential associations between poor oral health status (OHS) and increased pneumonia risk. Relative pneumonia risk was assessed in the context of longitudinally documented OHS. METHODS: Electronic medical/dental patient data captured from 2007 through 2019 were retrieved from the integrated health records of Marshfield Clinic Health Systems. Participant eligibility initiated with an assessment of OHS, stratified into the best, moderate, or worst OHS groups, with the additional criterion of 'no pneumonia diagnosis in the past 90 days'. Pneumonia incidence was longitudinally monitored for up to 1 year from each qualifying dental visit. Models were assessed, with and without adjustment for prior pneumonia incidence, adjusted for smoking and subjected to confounding mitigation attributable to known pneumonia risk factors by applying propensity score analysis. Time-to-event analysis and proportional hazard modeling were applied to investigate relative pneumonia risk over time among the OHS groups. RESULTS: Modeling identified associations between any incident pneumonia subtype and 'number of missing teeth' (p < 0.001) and 'clinically assessed periodontal status' (p < 0.01), which remained significant following adjustment for prior pneumonia incidence and smoking. The hazard ratio (HR) for 'any incident pneumonia' in the best OHS group for 'number of missing teeth' was 0.65, 95% confidence interval (CI) [0.54 - 0.79] (unadjusted) and 0.744, 95% CI [0.61 - 0.91] (adjusted). The HR for 'any incident pneumonia' in the best 'clinically assessed periodontal status' group was 0.72, 95% CI [0.58 - 0.90] (unadjusted) and 0.78, 95% CI [0.62 - 0.97] (adjusted). CONCLUSION/CLINICAL RELEVANCE: Poor OHS increased pneumonia risk. Proactive attention of medical providers to patient OHS and health literacy surrounding oral-systemic disease association is vital, especially in high-risk populations.