Pulmonary Damage Research Articles

Ameliorative impact of sacubitril/valsartan on paraquat-induced acute lung injury: role of Nrf2 and TLR4/NF-κB signaling pathway.

Herbicides such as paraquat (PQ) are frequently utilized particularly in developing nations. The present research concentrated on the pulmonary lesions triggered by PQ and the beneficial effect of the angiotensin receptor neprilysin inhibitor (ARNI), sacubitril/valsartan, against such pulmonary damage. Five groups of rats were established: control, ARNI, PQ (10 mg/kg), ARNI 68 + PQ, and ARNI 34 + PQ. Following euthanasia, lungs were isolated and subjected to a histopathological test, and the ELISA technique was used to evaluate oxidative stress biomarkers, toll-like receptor 4 (TLR4), nuclear factor erythroid 2-related factor 2 (Nrf2), phosphatidylinositol-3-kinase (PI3K), phosphorylated protein kinase B (p-AKT), and inflammatory markers: nuclear factor kappa B p65 subunit (NF-κB p65), tumor necrosis factor α (TNFα), and interleukin 1beta (IL-1β). In conjunction with abnormally high levels of malondialdehyde (MDA) and inducible nitric oxide synthase (iNOS), the PQ group also displayed low levels of reduced glutathione (GSH) and total antioxidant capacity (TAC). Additionally, TLR4, PI3K, and p-AKT were significantly elevated together with unusually low level of Nrf2. Moreover, inflammatory biomarkers, NF-κB p65, TNFα, and IL-1β, were abnormally elevated. Meanwhile, ARNI-treated groups reversed all alterations precipitated by PQ in a dose-dependent manner. ARNI could mitigate pulmonary damage triggered by PQ via potential antioxidant anti-inflammatory qualities.

Effect of ranolazine on cardiac remodeling and pulmonary artery pressure in patients with acute pulmonary embolism

Background. The development of right ventricular (RV) dysfunction is the most significant predictor of in-hospital mortality and one of the most important factors affecting the short- and long-term prognosis of pulmonary embolism (PE). Therefore, the development of treatment regimens aimed at inhibiting the progression of RV dysfunction and the fastest possible restoration of its function, as well as preventing the development and progression of pulmonary hypertension, is an important area of reducing mortality in acute PE. One of the most promising drugs that can theoretically reduce both RV and pulmonary damage is ranolazine. The purpose of the study was to evaluate the feasibility and efficacy of prescribing ranolazine to patients with PE, focusing on its impact on echocardiographic parameters. Materials and methods. The study included 70 patients diagnosed with acute PE verified bу CT pulmonary artery angiogram performed on the first 1–2 days and after 8–10 days of treatment. Patients were divided into two groups: group 1 consisted of 29 people who received ranolazine at a dose of 500 mg twice daily starting from day 1–2 of standard treatment, for 1 month; group 2 included 49 patients who did not receive ranolazine. All patients underwent a standard general clinical examination with an assessment of risk factors for PE and early death according to the 2019 European Society of Cardiology guidelines, with subsequent statistical processing of the data. Results. When analyzing the dynamics of indicators in the groups, a statistically significant decrease was found in the size of the right atrium (p = 0.0009), RV (p = 0.046), mean pulmonary artery pressure (mPAP) (p = 0.027), pulmonary artery systolic pressure (sPAP) (p = 0.00004) in the group 1. In the group without ranolazine, there also was a decrease in the size of the right atrium (p = 0.002), mPAP (p = 0.009), and sPAP (p = 0.03), but with no effect on the size of the RV. When comparing the difference in parameters on day 1 and 8–10, i.e., the shift of the parameters during treatment, a statistically significant decrease in sPAP was obtained in the ranolazine group compared to the group without its use (p = 0.03). Conclusions. Adding ranolazine to standard therapy for pulmonary embolism reduces right ventricular and atrial remodeling, as well as pulmonary artery pressure.

Autoantibody clusters in childhood-onset systemic lupus erythematosus: Insights from a multicenter study with 912 patients.

Objective: To identify clusters of autoantibodies in a large cSLE population and to verify possible associations between different autoantibody clusters and the following variables: demographic data, cumulative clinical and laboratory manifestations, disease activity, cumulative damage and mortality. Methods: A cross-sectional study was performed in 27 Pediatric Rheumatology University centers, including 912 cSLE patients. The frequencies of seven selected autoantibodies (anti-dsDNA, anti-Ro/SSA, anti-La/SSB, anti-Sm, anti-RNP, aCL IgM and/or IgG and LA) were used for cluster analysis using the K-means method. Results: Four distinctive antibody clusters were identified. Cluster 1 (n = 322; 35.31%) was characterized by anti-dsDNA (61.18%), low frequency of antiphospholipid antibodies (<10%), and lower frequency of cutaneous, articular manifestation (p < 0.05) and hypocomplementemia (p < 0.001) compared to the other groups. Cluster 2 (n = 158; 17.32%) comprised anti-dsDNA (93.04%), aCL (87.34%) and LA (39.87%) and higher frequencies of thrombocytopenia (p = 0.006) and antiphospholipid syndrome (p < 0.001) than the other clusters. Cluster 3 (n = 177; 19.41%) was characterized by anti-dsDNA (81.36%), anti-Sm (100%) and anti-RNP (44.63%) antibodies, as well as a higher frequency of proteinuria compared to cluster 4 (58.15% vs 56.13% vs 64.00% vs 49.80%, p = 0.031). Cluster 4 (n = 255; 27.96%) consisted of all 7 autoantibodies, with predominance of anti-dsDNA (72.55%), anti-Ro/SSA (89.8%) and anti-La/SSB (45.88%), with no specific clinical pattern, except by higher pulmonary damage (p = 0.017). Conclusions:Our study suggests that, within the context of cSLE, the coexistence of anti-dsDNA with antiphospholipid autoantibodies is linked to an elevated incidence of antiphospholipid syndrome. This association does not coincide with a proportionate increase in the occurrence of nephritis. Conversely, the cluster of anti-dsDNA with anti-Ro/SSA and anti-La/SSB antibodies was associated with pulmonary damage, requiring close surveillance.

Yunvjian decoction attenuates lipopolysaccharide-induced acute lung injury by inhibiting NF-κB/NLRP3 pathway and pyroptosis

IntroductionYunvjian (YNJ) decoction, a classic traditional Chinese medicine prescription for inflammatory diseases, has demonstrated good therapeutic effects in the clinical treatment of pneumonia. The aim of this study was to clarify the effective ingredients and mechanism of action of YNJ on lipopolysaccharide (LPS)-induced acute lung injury (ALI).MethodsThe effects of YNJ were evaluated in a mouse model of LPS-induced ALI and in LPS-treated MLE-12 murine lung epithelial cells and RAW264.7 macrophages in vitro. The mechanism of action of YNJ on these model systems was studied using RNA sequencing, immunohistochemical analysis, immunoblotting, immunofluorescence, ELISA, and polymerase chain reaction assays. Ultra-high performance liquid chromatography coupled with quadrupole time-of-flight mass spectrometry was applied to identify the absorbed components of YNJ.ResultsYNJ attenuated pulmonary damage in LPS-treated mice, as evidenced by reduced protein content in bronchoalveolar lavage fluid, decreased lung wet/dry weight ratio, and improved respiratory function. Analysis of pneumonia-related lung injury samples from patients in the Gene Expression Omnibus dataset GSE40012 indicated that NOD-like receptor protein 3 (NLRP3)-mediated pyroptosis was a primary mechanism in ALI. YNJ reduced the phosphorylation of nuclear factor-kappa B (NF-κB) and decreased the expression levels of lung NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), cleaved caspase-1, and interleukin-1β levels (IL-1β) in vivo. Administration of YNJ-containing mouse serum increased cell viability and decreased malondialdehyde and reactive oxidative species contents in LPS-stimulated MLE-12 cells. YNJ-containing serum also decreased the secretion of tumor necrosis factor-α, IL-6, and IL-1β in LPS-stimulated RAW264.7 macrophages, and promoted macrophage polarization toward an M2 phenotype. A total of 23 absorbed components were identified in YNJ-containing serum. Among those, network analysis and in vitro experiments indicated that diosgenin, timosaponin BII, and mangiferin are anti-inflammatory active substances.ConclusionYNJ attenuates LPS-induced ALI in mice by inhibiting pyroptosis of lung epithelial cells and macrophages via suppression of the NF-κB/NLRP3 pathway. Our findings provide novel insights into the therapeutic effects of YNJ on ALI.

Effect of nanocurcumin (Curcuma longa) on lung histopathology in rats exposed to carbon black

Background Exposure to carbon black can induce respiratory toxicity, leading to tissue remodeling, inflammation, and fibrosis. Curcumin, a compound from Curcuma longa, has been shown to exert protective effects on lung tissue by inhibiting cell proliferation and reducing alveolar epithelial thickening and inflammatory responses. Objective This study aimed to evaluate the effect of nanocurcumin administration on alveolar septal thickness and fibrosis in the lungs of rats (Rattus norvegicus) exposed to carbon black. Methods Thirty female rats were divided into five groups: the negative control group (K-) received distilled water without carbon black exposure; the positive control group (K+) received distilled water and was exposed to carbon black at a dose of 1064 mg/m³ for 6 hours; and treatment groups P1, P2, and P3 received nanocurcumin at doses of 50, 100, and 200 mg/kg body weight, respectively, along with carbon black exposure at a dose of 1064 mg/m³ for 6 hours/day over 30 days. Results Alveolar septal thickness and fibrosis in the P1, P2, and P3 groups showed significant reductions (P&lt;0.05) compared to the K+ group. Notably, groups P2 and P3 exhibited similar alveolar septal thickness to the K- group, with statistically lower (P&lt;0.05) fibrosis levels than P1 but not significantly different from K- (P&gt;0.05). Conclusion Nanocurcumin administration demonstrates potential in mitigating alveolar septal thickening and fibrosis in rat lungs subjected to carbon black exposure, suggesting a protective role against pulmonary damage from particulate matter.

Immunological Insights and Therapeutic Advances in COPD: Exploring Oral Bacterial Vaccines for Immune Modulation and Clinical Improvement

Chronic obstructive pulmonary disease (COPD) is a prevalent chronic condition associated with substantial global morbidity and mortality. Primarily caused by prolonged exposure to harmful agents such as dust and gases, COPD is characterized by persistent airflow limitation, clinically manifesting as chronic cough, sputum production, and dyspnea. The disease course alternates between stable phases and exacerbations, with the latter often associated with pathogenic colonization of the respiratory tract. This review examines the immunological underpinnings of COPD, emphasizing the interplay between innate and adaptive immunity in disease pathogenesis. Dysregulated immune responses to environmental factors perpetuate chronic inflammation, resulting in progressive pulmonary epithelial damage and connective tissue hyperplasia, which compromise gas exchange. Exacerbations further exacerbate respiratory failure, aggravating patient symptoms and accelerating disease progression. Despite advances in COPD management, effective therapeutic options remain limited. Current treatments primarily aim to alleviate symptoms, reduce immune activation, and manage infections, yet many patients experience suboptimal outcomes. This review highlights the potential of novel therapeutic approaches targeting immune system cells and pathways. In particular, it explores the promise of oral bacterial vaccines as immunomodulatory agents to enhance immune responses and improve clinical outcomes in COPD, addressing critical gaps in current treatment paradigms.

Ultrasonographic evaluation of the thorax in dogs with tick paralysis

Tick paralysis is a rapidly progressing motor paralysis caused by a neurotoxin in the saliva of certain tick species. Delayed diagnosis can lead to increased mortality due to respiratory failure. Thus, the aim of this study is to describe thoracic ultrasonography lesions in dogs with tick paralysis and to identify potential patterns that could aid in diagnosis and prognosis prediction. The animal material consisted of 58 dogs in total, 10 of which were healthy and 48 of which were suspected to be affected by tick paralysis. Clinical, laboratory and thoracic ultrasonographic examinations were performed. Expiratory dyspnea with sinus tachycardia; fine crackles, polyphonic wheezing, and pleural rub on lung auscultation were observed in the tick–paralyzed dogs. The most common abnormal thoracic ultrasonography patterns were, in order of prevalence: B–lines &gt; 3, wet lung, pulmonary nodule, confluent B–lines, loss of A–lines, consolidation, fibrosis, and isolated B–lines. In addition, the pleural thickness of the tick–paralyzed dogs was higher than that of the healthy ones. Among these findings, B–lines &gt; 3 were interpreted as indicative of possible pulmonary parenchymal damage, while the loss of A–lines was attributed to decreased aeration. The presence of pulmonary nodule and fibrosis might be due to bronchopneumonia and aspiration pneumonia due to regurgitation. The wet lung pattern was associated with a predisposition to lung congestion. It was concluded that recognizing thoracic ultrasonography findings may assist in identifying the presence and grading the extent of lung damage, as well as determining the necessity of lung decongestion treatment in tick paralysis cases.

Investigation of the sclerosing effect of increasing doses of polidocanol on pulmonary vessels: Experimental study.

Percutaneous sclerotherapy as endovascular treatment may cause severe complications beside the target area. Pulmonary embolism and thrombosis may occur. In this regard, our study aimed to reveal whether increasing systemic doses of polidocanol affects the coronary or pulmonary alveolar levels. Twenty-one Albino New Zealand rabbits, 7 rabbits per group, were used. The first group served as a control and received a 0.5 mL injection of saline; the second group received a single injection of 0.5 mL 1% polidocanol; and the third group received a single injection of 0.5 mL 2% polidocanol via the femoral vein. After anesthesia-induced decapitation on day 3, the experimental rabbits' lungs were removed in their entirety and sent to pathology for analysis. Micron-thick slices. In all lung specimens of the first 2 groups, no narrowing or obstruction was detected in the pulmonary vessels in macroscopic and microscopic evaluation. No emphysematous changes or congestion were observed. In the third group's animal lungs, congestion in pulmonary vessels, emphysematous changes, and intra-alveolar hemorrhage were found. In our study, a single injection of 0.5 mL 2% polidocanol via the femoral vein. Animal lungs, congestion in pulmonary vessels, emphysematous changes, and intra-alveolar hemorrhage were found. As a result, our study demonstrated pulmonary vascular damage with increasing doses of polidocanol. So, the dose of polidocanol should be used in a limited manner.

Serum Biomarkers of Pulmonary Damage and Risk for Progression of Rheumatoid Arthritis-Associated Interstitial Lung Disease.

To investigate baseline and change of pulmonary damage biomarkers (serum Krebs von den Lungen 6 [KL-6], human surfactant protein D [hSP-D], and matrix metalloproteinase 7 [MMP-7]) with rheumatoid arthritis-associated interstitial lung disease (RA-ILD) progression. In the Korean Rheumatoid Arthritis Interstitial Lung Disease (KORAIL) cohort, a prospective cohort, we enrolled patients with RA and ILD confirmed by chest computed tomography imaging and followed annually. ILD progression was defined as worsening in physiological and radiological domains of the 2022 American Thoracic Society, European Respiratory Society, Japanese Respiratory Society, and Latin American Thoracic Society guideline for progressive pulmonary fibrosis (PPF). Associations between biomarkers and RA-ILD progression were analyzed using multivariable Cox regression, adjusting for potential confounders. We analyzed 136 patients with RA-ILD (mean age 66.5 yrs, 30% male, 60.3% with usual interstitial pneumonia pattern). During a median 3.0 years of follow-up, 47 patients (34.6%) experienced progression. Higher baseline KL-6 and hSP-D levels were associated with higher risk of ILD progression (multivariable hazard ratios [HRs] 1.37 [95% CI 1.03-1.82] and 1.51 [95% CI 1.09-2.08], respectively), whereas only the highest quartile of MMP-7 showed an increased risk (multivariable HR 2.60 [95% CI 1.07-6.33]). Increasing levels of serum KL-6 at 1 year showed the strongest association with progression (ΔKL-6: multivariable HR 2.00 [95% CI 1.29-3.11]), additionally adjusting for baseline biomarker levels. In this first prospective study to apply PPF criteria to RA-ILD, 34.6% progressed over 3 years. Higher baseline KL-6 and hSP-D were associated with progression. In follow-up, greater change in KL-6 was associated with progression. Serial measurement of pulmonary damage biomarkers may predict RA-ILD progression and may be helpful in monitoring patients and treatment decisions.

A novel technique of cryodenervation for murine vagus nerve: implications for acute lung inflammation

BackgroundNeuroimmune interaction is an underestimated mechanism for lung diseases, and cryoablation is a competitive advantageous technique than other non-pharmacologic interventions for peripheral nerve innervating the lung. However, a lack of cryodenervation model in laboratory rodents leads to the obscure mechanisms for techniques used in clinic.MethodHerein, we developed a novel practical method for mouse peripheral nerve cryoablation, named visualized and simple cryodenervation (VSCD). We first estimated the feasibility, safety and effectiveness of the technique via haematoxylin-eosin staining, histochemistry or immunofluorescence staining and immunoblotting assay. We then constructed the acute lung injury (ALI) model triggered by lipopolysaccharide (LPS) to verify the effect of VSCD in the resolution of pulmonary inflammation. Besides, the IL-10 knockout mice were also applied to explain the underlying mechanism of the protective activity of VSCD in ALI mice.ResultWe demonstrated that VSCD was able to induce a reliable and stable blockade of innervation, but reversible structural damage of mouse vagus nerve without detectable toxicity to lung tissues. Cholinergic parasympathetic nerve in the mouse lung coming from vagus nerve was activated at the initial stage (1 week) after VSCD, and blocked 3 weeks later. By use of the ALI mouse model, we found that VSCD effectively decreased pulmonary inflammation and tissue damage in the ALI mice. Moreover, the activated cholinergic anti-inflammatory pathway (CAP) and elevated IL-10 expression might explain the protective action of VSCD following LPS challenge.ConclusionThis study fills the gap in the cryoablation for mouse vagus nerve, thereby guiding the application of cryodenervation in clinical management of pulmonary diseases. It also offers evidence of anti-inflammatory potential of VSCD in ALI mouse model and opens therapeutic avenues for the intervention of acute lung inflammation.

Ginsenoside Rb1 targets to HO-1 to improve sepsis by inhibiting ferroptosis

Sepsis remains the leading cause of mortality among Intensive Care Unit (ICU) patients, with its pathogenesis and treatment not yet fully elucidated. Ferroptosis plays a critical role in sepsis, suggesting that ferroptosis-related genes may serve as potential therapeutic targets. This study aims to identify key ferroptosis-related genes in sepsis and explore targeted therapeutics. Through differential expression analysis of the GSE13940 and GSE26440 datasets, heme oxygenase-1 (HO-1) was identified as a hub gene associated with ferroptosis. Additionally, single-cell analysis of the GSE175453 dataset revealed a significant upregulation of HO-1 expression in monocyte lineages during sepsis. The cecal ligation and puncture (CLP) method was employed to induce sepsis in a mouse model, lung and intestinal tissues exhibited typical ferroptosis characteristics, with a significant increase in HO-1 expression. However, treatment with the HO-1 inhibitor zinc protoporphyrin (ZNPP) significantly ameliorated ferroptosis in CLP-induced lung and intestinal tissues, as well as in lipopolysaccharide (LPS)-induced THP-1 cells. Subsequently, molecular docking, surface plasmon resonance (SPR), and microscale thermophoresis (MST) experiments demonstrated that ginsenoside Rb1 specifically targets HO-1, identifying K18A as the key binding residue. Finally, experiments conducted both in vitro and in vivo verified that ginsenoside Rb1 significantly reduces HO-1 expression, inhibits ferroptosis in sepsis-induced lung, and intestinal tissues and THP-1 cells, and improves sepsis-induced pulmonary and intestinal damage. In conclusion, this study identifies HO-1 as a key ferroptosis target in sepsis and suggests ginsenoside Rb1 as a potential novel HO-1 inhibitor for the therapeutic approach of sepsis-induced organ dysfunction.

Recombinant RAGE antagonist peptide promotes alveolar epithelial cell regeneration via the RAGE/MAPKs/MMP2 pathway in emphysema

The progression of chronic obstructive pulmonary disease (COPD) results in irreversible pulmonary damage and sustained inflammatory responses. While alternative approaches have been explored, the specific role of alveolar epithelial cells in the pathogenesis of COPD remains unclear. Additionally, the association between emphysema and DAMP-RAGE signaling in COPD patients are not understood. Therefore, this study demonstrates to determine the therapeutic effect of a RAGE antagonist peptide (RAP), which we previously identified on the pathogenesis of COPD. We assessed the expression of RAGE ligands and RAGE binding signaling in COPD patients using GEO data. PPE-induced emphysema mouse model and AGER-/- mouse were employed, along treated with RAP. The association between RAGE and the development of emphysema was examined in H&E staining and western blot analysis in mouse lung tissue and BALF. We next analyzed the damage caused by oxidative stress and inflammation through CSE and RAP in human alveolar epithelial cell line A549. Our results show that inhibiting of RAGE alleviates emphysema by suppressing inflammation and MMP activity. Inhibition of RAGE in alveolar epithelial cells significantly induced the mitigation of lung injury, independent of macrophage infiltration. Furthermore, it was confirmed that RAP ameliorated CSE-induced oxidative stress, inflammation, and cell cycle arrest in human alveolar epithelial cells. These findings demonstrate that inhibiting RAGE in alveolar epithelial cells suppress lung injury and emphysema by inhibiting oxidative stress-induced inflammation and MMPs, while promoting alveolar epithelial cell proliferation. Furthermore, blocking of the DAMP-RAGE interaction through RAP offers a promising therapeutic approach for mitigating emphysema.

Quantitative IgG response to SARS-CoV-2 membrane protein in infected individuals strongly correlates with lung injury

The clinical manifestations of SARS-CoV-2 infection may range from asymptomatic or minor conditions to severe and life-threatening outcomes. The respiratory system is a principal target of the virus and in the majority of cases of severe disease, an acute form of pneumonia develops. Despite concerted global efforts to elucidate the pathogenic mechanisms of COVID-19, the progression of the infection leading to pulmonary damage remains poorly understood. The present study aimed to analyse the immunological profile of subjects with a previous SARS-CoV-2 infection and predisposition to lung injury. The results showed a strong correlation between IgG anti-membrane antibodies and lung injury.

SARS-CoV-2 specific adaptations in N protein inhibit NF-κB activation and alter pathogenesis.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and severe acute respiratory syndrome coronavirus (SARS-CoV) exhibit differences in their inflammatory responses and pulmonary damage, yet the specific mechanisms remain unclear. Here, we discovered that the SARS-CoV-2 nucleocapsid (N) protein inhibits the activation of the nuclear factor-κB (NF-κB) pathway and downstream signal transduction by impeding the assembly of the transforming growth factor β-activated kinase1 (TAK1)-TAK1 binding protein 2/3 (TAB2/3) complex. In contrast, the SARS-CoV N protein does not impact the NF-κB pathway. By comparing the amino acid sequences of the SARS-CoV-2 and SARS-CoV N proteins, we identified Glu-290 and Gln-349 as critical residues in the C-terminal domain (CTD) of the SARS-CoV-2 N protein, essential for its antagonistic function. These findings were further validated in a SARS-CoV-2 trans-complementation system using cellular and animal models. Our results reveal the distinctions in inflammatory responses triggered by SARS-CoV-2 and SARS-CoV, highlighting the significance of specific amino acid alterations in influencing viral pathogenicity.

Evaluating the Efficacy and Safety of Baricitinib in Reducing COVID-19 Mortality: A Comprehensive Review of Clinical Evidence and Pharmacological Strategies

Introduction: COVID-19 manifests with symptoms ranging from mild to severe, including respiratory and cardiovascular complications. Severe cases are often marked by a cytokine storm, causing pulmonary damage and multi-organ dysfunction. Current treatments lack a specific antiviral, though several pharmacological options, including immunomodulatory and antiviral drugs, are under investigation. Purpose: The purpose of this article is to provide an evaluation of the efficacy and safety of baricitinib, a JAK inhibitor, combined with standard care for hospitalized adults with COVID-19. By reviewing recent literature, it aims to assess baricitinib's effectiveness in improving patient outcomes. Material and methods: A systematic review of clinical trials and case studies was conducted to analyze baricitinib’s impact on COVID-19 mortality. Data includes treatment-emergent adverse events and patient outcomes in moderate to severe cases. Discussion: Baricitinib has demonstrated potential in managing hyperinflammation in severe COVID-19 by inhibiting multiple proinflammatory cytokines and enhancing immune response. Clinical trials show that baricitinib, particularly in combination with corticosteroids, reduces mortality and serious infections compared to standard care alone. Due to potential adverse events, continuous monitoring of hematological and lipid levels is essential. These findings highlight baricitinib's dual role as an immunomodulatory and antiviral agent, suggesting its importance in treating severe COVID-19. Future research should focus on optimizing treatment regimens and further exploring the long-term implications of baricitinib therapy.

Neutral Polysaccharide from Platycodonis Radix-Ameliorated PM2.5-Induced Lung Injury by Inhibiting the TLR4/NF-κB p65 Pathway and Regulating the Lung and Gut Microbiome.

Platycodonis radix (PR) has been reported to play a protective role in lung injury. However, much less is known about the protective effect and mechanism of its main component PR polysaccharides (PRPs) in particulate matter (PM2.5)-induced lung injury. Here, a neutral polysaccharide (MW: 244.56 kDa) was isolated from PR, mainly composed of Rha, Ara, Gal, Glc, Xyl, and Man. PRPs significantly improved PM2.5-induced pulmonary edema, oxidative damage, and cell apoptosis and downregulated inflammatory factor levels in bronchoalveolar lavage fluid. Mechanistically, PRPs reduced intestinal mucosal barrier damage, thereby lowering serum lipopolysaccharide levels and inhibiting the overactivation of the TLR4/NF-κB signaling pathway in the lung tissue. Notably, PRPs could optimize the composition of pulmonary and intestinal microbiota. Oral administration of PRPs resulted in enrichment of short-chain fatty acid (SCFA)-producing bacteria, thereby upregulating the levels of acetate, butyrate, and isovalerate. Taken together, PRPs have great potential in preventing and repairing the lung injury caused by PM2.5.

N6-methyladenosine mediated-NRF2 signaling pathway attenuates cadmium cytotoxicity by inhibiting oxidative damage in bronchial epithelial cells.

Although N6-methyladenosine (m6A) and its regulatory proteins were involved in multiple cellular damage processes, the roles of m6A and its regulatory proteins in cadmium-induced pulmonary cell damage remain largely unknown. Our present data indicated that cadmium exposure caused serious damage in bronchial epithelial cells, as evidenced by reduction of cell viability and elevation of oxidative damage and apoptosis. These processes were accompanied by alterations of m6A modification and its regulatory proteins (FTO, ALKBH5, YTHDC2). It is noteworthy that pretreatment with the m6A agonist entacapone (ENT) markedly attenuated the detrimental effects of cadmium, including cell death, oxidative damage, and the activation of the nuclear factor erythroid 2-related factor 2(NRF2）signalling pathway. Conversely, the detrimental effects of CdSO4 were significantly exacerbated when m6A levels were inhibited by 3-deazidyladenosine (DAA). Further prediction result revealed that multiple m6A-modified sites occur on NRF2 mRNA with high confidence level, implicating that m6A modification on NRF2 mRNA may affect the protein expression of NRF2. In conclusion, our data together suggest that m6A modification play critical roles in cadmium-induced bronchial epithelial cell damage, during which NRF2 signaling pathway may act as an important bridge for m6A modification to regulate cellular damage. This study offer a promising avenue for further investigation into the mechanisms underlying cadmium-induced bronchial epithelial cell damage from the perspective of RNA epigenetics.

Effect of imatinib on lipopolysaccharide‑induced acute lung injury and endothelial dysfunction through the P38 MAPK and NF-κB signaling pathways in vivo and in vitro.

The primary purpose of this study was to demonstrate the preventive effects of imatinib (IMA) on lipopolysaccharide (LPS)-induced inflammation in a mouse model of acute lung injury (ALI) and human umbilical vascular endothelial cells. LPS stimulation for 24h induced ALI and cell inflammation. The pathological results of the lungs were evaluated using the wet/dry weight ratio, pulmonary vascular permeability measurements, and myeloperoxidase immunohistochemistry. The expression of pro-inflammatory mediators was analyzed using RT-PCR and enzyme-linked immunosorbent assay. Protein levels were analyzed using western blotting. The structure of cell junctions was detected using immunofluorescence. IMA improved LPS-induced pulmonary pathological damage and reduced the lung wet/dry weight ratio and myeloperoxidase expression in the lung tissue. IMA decreased bronchoalveolar lavage fluid inflammatory cell count and the release of tumor necrosis factor-α (TNF-α), interleukin (IL)-6, and monocyte chemotactic protein 1 (MCP-1) in the blood. Pretreatment of human umbilical vascular endothelial cells with IMA significantly attenuated LPS-induced actin stress fiber formation and vascular endothelial-cadherin disruption. In addition, IMA downregulated the mRNA abundances of vascular cell adhesion molecule 1, intercellular adhesion molecule 1, IL-1β, IL-6, and tumor necrosis factor-α(TNF-α) expression. The phosphorylation of p65, nuclear factor-kappa B inhibitor alpha (IκBα), p38, extracellular signal-regulated kinase, and Jun N-terminal kinase induced by LPS were attenuated after IMA treatment in vivo and in vitro. IMA modulates the nuclear factor-kappa B and mitogen-activated protein kinase signaling pathways and the production of pro-inflammatory cytokines to prevent cellular damage due to LPS infection. These results indicate that IMA may be a potential modulator of LPS-induced ALI.

Ambient PM2.5 orchestrates M1 polarization of alveolar macrophages via activating glutaminase 1-mediated glutaminolysis in acute lung injury.

The temporary explosive growth events of atmospheric fine particulate matter (PM2.5) pollution during late autumn and winter seasons still frequently occur in China. High-concentration exposure to PM2.5 aggravates lung inflammation, leading to acute lung injury (ALI). Alveolar macrophages (AMs) participate in PM2.5-induced pulmonary inflammation and injury. The polarization of AMs is dependent on metabolic reprogramming. However, the mechanism underlying the PM2.5-induced glutaminase-mediated glutaminolysis in AM polarization is still largely obscure. In this study, we found that PM2.5-treated mice exhibited pulmonary dysfunction and inflammation. The concentrations of glutamate and succinate were increased in PM2.5-treated lungs and AMs compared with the controls, whereas glutamine and α-ketoglutarate (α-KG) levels were decreased, indicating that glutaminolysis in AMs was aberrantly activated as evidenced by increased mRNA and protein levels of GLS1 after PM2.5 exposure. Moreover, we determined that the GLS1/nuclear factor kappa-B (NF-κB)/hypoxia-inducible factor-1α (HIF-1α) pathway regulated M1 polarization of AMs upon PM2.5 exposure. Inhibition of glutaminolysis by GLS1 specific inhibitor CB-839 and GLS1 siRNA significantly decreased PM2.5-induced M1 macrophage polarization and attenuated pulmonary damage. Taken together, our findings reveal a novel mechanism by which a metabolic program regulates M1 polarization of AMs and suggest that GLS1-mediated glutaminolysis is a potential therapeutic target for treating PM2.5-induced ALI.

Prediction of impaired lung diffusion capacity in COVID-19 pneumonia survivors.

Patients surviving the coronavirus disease 2019 (COVID-19) are reported to explore pulmonary sequelae. It is challenging to provide pulmonary function tests (PFTs) during the pandemic of this contagious diseases because of the difficulty related to infection control risks. This study aims to identify important predictors of lung diffusion capacity impairment in COVID-19 survivors after hospital discharge. The retrospective cohort study included 341 patients after COVID-19. The parameters of spirometry, body plethysmography, lung diffusion capacity for carbon monoxide (DLco), and the worst chest computed tomography (CT) scan in the acute phase of COVID-19 (CTmax, %) were assessed. Multivariable logistic regression analysis for exploring risk factors associated with lung diffusion capacity impairment was used. The receiver operating characteristic (ROC) curve of multivariate observation and the area under the curve (AUC) were used to assess the performance of a model. At the time of the analysis, 64.8% (221/341) patients participated in follow-up visits on 90 days, 23.5% (80/341) on 90-180 days, and 11.7% (40/341) on more than 180 days after the onset of COVID-19 symptoms. The median CTmax was 50% (50% of the lung area was involved in a pathological process according to a semi-quantitative CT score). Abnormal DLco (<80% of predicted) was recorded in 60.4% cases. The predictors such as age, gender, body mass index (BMI), CTmax, and the time interval between the COVID-19 symptoms onset and follow-up PFTs were encapsulated in the logistic regression analysis to explore the prediction of reduced DLco. Backward stepwise regression was applied to eliminate insignificant predictors. It was found that CTmax was important predictor of impaired DLco. AUC value was 0.780 [95% confidential interval (CI): 0.723-0.837, P<0.001]. The sensitivity and specificity in the training group were 80% and 67%, respectively. The odds ratio (OR) showed that CTmax =45% and more in the acute phase of COVID-19 was significantly associated with reduced DLco during 6 months after COVID-19 (OR 1.21, 95% CI: 1.095-1.334; P<0.05). Pulmonary interstitial damage caused by severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) definitely contributes to reduced DLco after hospital discharge. This indicates that analysis of CT scans during the acute phase of COVID-19 may have prognostic relevance for abnormal DLco.