Alterations In Lung Tissue Research Articles

Porcine Nose Atrophy Assessed by Automatic Imaging and Detection of Bordetella bronchiseptica and Other Respiratory Pathogens in Lung and Nose.

The nasal mucosa is a crucial filtering organ to prevent attachment and invasion of pathogens. To assess nasal health in relation to lung health, transverse cross sections of the nasal turbinates of 121 pigs suffering from respiratory disease and sent for diagnostic necropsy were scored visually and by an artificial intelligence (AI) medical diagnostic application (AI DIAGNOS), resulting in a high correlation of both scores (p < 0.001). Nasal samples of the diseased pigs were examined only for Bordetella (B.) bronchiseptica (PCR and bacteriological culture) and Pasteurella (P.) multocida (bacteriological culture). All pigs showed various degrees of inflammatory lung tissue alterations, and 35.5% of the pigs had atrophy of the nasal turbinates with no relation to detection rates of B. bronchiseptica (54.5%) and P. multocida (29.0%) in the nose. All P. multocida strains from nose samples were negative for the toxA gene so non-progressive atrophic rhinitis was diagnosed. Pigs positive for B. bronchiseptica in the nose were more often positive for B. bronchiseptica in the lung (p < 0.001) and for other bacterial species in the lower respiratory tract (p = 0.005). The new diagnostic application for scoring cross sections of nasal turbinates is a valuable tool for a fast and reproducible diagnostic.

Trigonelline mitigates bleomycin-induced idiopathic pulmonary fibrosis in mice

Objective: To evaluate the effect of trigonelline on bleomycin-induced idiopathic pulmonary fibrosis (IPF) and to explore its underlying mechanisms using network pharmacology. Methods: IPF was induced in C57BL/6 mice by a single intratracheal instillation of bleomycin (5 mg/kg). Trigonelline was administered at doses of 25, 50, and 100 mg/kg/day orally from the 2nd day post-bleomycin induction up to the 14th day. In IPF-induced mice, lung coefficient, immune cell infiltration in bronchoalveolar lavage fluid, and oxidative stress were measured. Histological alterations in lung tissues were also assessed. Moreover, network pharmacology approach was conducted to reveal molecular interactions of bleomycin and trigonelline with targets of IPF. Results: Trigonelline treatment reduced bleomycin-induced oxidative stress and immune cell infiltration, and mitigated physiological changes in the lung tissues of mice. Moreover, trigonelline alleviated bleomycin-induced histological alterations in lung tissues. Network pharmacology analysis showed that bleomycin and trigonelline interacted with IPF targets, such as NFKB1, HDAC2, HIF1A, and TLR4. Conclusions: The interaction of trigonelline with key IPF targets and its ameliorative effects on lung damage and oxidative stress highlight its potential in treating IPF. It may be considered an antifibrotic agent for further clinical development.

Artemisia argyi essential oil alleviates asthma by regulating 5-LOX-CysLTs and IDO-1-KYN pathways: Insights from metabolomics

Ethnopharmacological relevanceArtemisia argyi essential oil (AAEO) is a traditional herbal remedy for asthma. However, the potential effect of AAEO on asthma has not been elucidated. Aim of the studyTo investigate the protective properties of AAEO upon asthma and elucidate its mechanism. Materials and methodsThe effects of AAEO in asthma were assessed by histology and biochemical analysis. Then, we integrated real-time reverse transcription-quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, immunohistochemistry and metabolomics analysis to reveal its mechanism. ResultsIn vivo, AAEO reduced the counts of white blood cells (WBCs) and cytokines in bronchoalveolar lavage fluid (BALF), ameliorated pathologic alterations in lung tissues, and inhibited secretion of OVA-sIgE and muc5ac. Metabolomics results showed that AAEO can exert therapeutic effects on asthmatic mice by regulating disordered arachidonic acid metabolism and tryptophan metabolism. Further studies shown that AAEO inhibited the expression of 5-LOX and reduced the accumulation of CysLTs in mice. Meanwhile, AAEO promoted the activity of IDO-1, facilitated the conversion of tryptophan to kynurenine, and regulated the imbalance of Treg/Th17 immunity. Immunohistochemical results showed that AAEO promoted the expression of IDO-1. RT-qPCR results showed that AAEO promoted the expression of IL-10 and Foxp3 mRNA, and inhibited the expression of IL-17A and RORγt mRNA, thus regulated the imbalance of Treg/Th17 immunity and exerted its therapeutic effects. ConclusionAAEO treatment not only attenuates the clinical symptoms of asthma but is also involved in regulating lung tissue metabolism. The anti-asthmatic activity of AAEO may be achieved by reprogramming 5-LOX-CysLTs and IDO-1-KYN pathways.

Staging of COVID-19 morphological manifestations in lungs depending on disease duration

To determine morphological alterations in lung tissues in the case of novel coronavirus infection (COVID-19) in the aspect of process staging with consideration to disease duration. The number of COVID-19-related deaths of patients aged 55-65 years equal 17 were investigated. Serial cuts of lung tissue stained with hematoxylin and eosin, obtained from several lung fragments of each corpse, were analyzed. Morphological features previously described in literature sources were taken into account. It has been established, that processes in lungs have a phasic character, furthermore they are not clearly delimited in time. In addition, there were no morphological features specific to COVID-19. Obtained results may allow forensic medical experts-histologists to predict the COVID-19 duration.

Exploring the Mechanisms of Modified Bu-Shen-Yi-Qi Decoction for COPD-Related Osteoporosis Therapy via Transcriptomics and Network Pharmacology Approach.

To investigate the effectiveness of modified Bu-Shen-Yi-Qi decoction (MBSYQ) in the treatment of osteoporosis associated with chronic obstructive pulmonary disease (COPD) and its underlying mechanisms of action. Disease targets, active ingredients and targets were predicted by TTD, CTD, DisGeNET, HERB (BenCaoZuJian as its Chinese name), and multiple-TCM databases; In addition, the screened targets were performed via the online platforms DAVID 6.8 and Metascape for GO and KEGG pathway enrichment analysis; The relationship between the MBSYQ and core targets were verified by molecular docking technique. Then we established a COPD-associated osteoporosis rat model by passive 24-week cigarette exposure. We assessed the efficacy of MBSYQ by lung histopathology assessment and distal femur/the first lumbar vertebra (L1) microstructural assay. In addition, we performed tibial RNA sequencing, which was validated by RT-PCR and Western blot. Screening revealed that the 350 active compounds of MBSYQ anchored 228 therapeutic targets for COPD-related osteoporosis; KEGG pathway enrichment analysis showed that the key targets mainly regulated MAPK and PI3K/AKT signaling pathways. In vivo studies showed that MBSYQ treatment alleviated pathological alterations in lung tissue, and reversed the bone loss and microstructure damage in the femur/L1 of model rats. The RNA seq indicated that MBSYQ could upregulate genes associated with anti-oxidative stress and aerobic respiration. The GSEA analysis displayed that MAPK and PI3K/AKT pathways were inhibited by CS exposure and activated by MBSYQ. MBSYQ is effective in the prevention and treatment of COPD-related osteoporosis, partially achieved by improving oxygen metabolism and activating MAPK and PI3K/AKT pathways.

Glutamine inhibits inflammation, oxidative stress, and apoptosis and ameliorates hyperoxic lung injury.

Glutamine (Gln) is the most widely acting and abundant amino acid in the body and has anti-inflammatory properties, regulates body metabolism, and improves immune function. However, the mechanism of Gln's effect on hyperoxic lung injury in neonatal rats is unclear. Therefore, this work focused on examining Gln's function in lung injury of newborn rats mediated by hyperoxia and the underlying mechanism. We examined body mass and ratio of wet-to-dry lung tissue weights of neonatal rats. Hematoxylin and eosin (HE) staining was performed to examine histopathological alterations of lung tissues. In addition, enzyme-linked immunoassay (ELISA) was conducted to measure pro-inflammatory cytokine levels within bronchoalveolar lavage fluid (BALF). Apoptosis of lung tissues was observed using TUNEL assay. Western blotting was performed for detecting endoplasmic reticulum stress (ERS)-associated protein levels. The results showed that Gln promoted body weight gain, significantly reduced pathological damage and oxidative stress in lung tissue, and improved lung function in neonatal rats. Gln reduced pro-inflammatory cytokine release as well as inflammatory cell production in BALF and inhibited apoptosis in lung tissue cells. Furthermore, we found that Gln could downregulate ERS-associated protein levels (GRP78, Caspase-12, CHOP) and inhibit c-Jun N-terminal kinase (JNK) and inositol-requiring enzyme 1 alpha (IRE1α) phosphorylation. These results in an animal model of bronchopulmonary dysplasia (BPD) suggest that Gln may have a therapeutic effect on BPD by reducing lung inflammation, oxidative stress, and apoptosis and improving lung function; its mechanism of action may be related to the inhibition of the IRE1α/JNK pathway.

Isoegomaketone alleviates inflammatory response and oxidative stress in sepsis lung injury.

Sepsis is a life-threatening condition characterized by acute organ dysfunction, which frequently leads to acute lung injury (ALI) in approximately 40% of cases. Isoegomaketone (IK) is a constituent of essential oil found in P. frutescens, known for its diverse biological properties, including anti-inflammatory and antitumor effects. However, the regulatory impact of IK on ALI in the context of sepsis remains poorly understood. Pathological alterations in lung tissues were assessed using hematoxylin and eosin staining. Enumeration of total leukocytes and neutrophils in bronchoalveolar lavage fluid (BALF) was performed using a hematocytometer, while the levels of interleukin (IL)-6, IL-1β, IL-10, and IL-17 in BALF were quantified using enzyme-linked immunosorbent serological assay. In addition, the levels of malondialdehyde (MDA), myeloperoxidase (MPO), superoxide dismutase (SOD), and glutathione (GSH) in lung tissues were assessed using respective commercial kits; cell apoptosis was evaluated using the terminal deoxynucleotide transferase--mediated dUTP nick end-labeling assay, and protein expressions were determined through Western blot analysis. Our findings revealed that cecal ligation and puncture (CLP) treatment in mice induced severe lung injury, characterized by increased lung injury scores, significant bleeding, neutrophil infiltration, and alveolar edema. However, treatment with IK at a dose of 10 mg/kg ameliorated CLP-induced lung injury, while IK dose of 5 mg/kg showed no significant effect. Additionally, IK treatment at 10 mg/kg reduced CLP-induced inflammation by decreasing levels of IL-6, IL-1β, IL-10, and IL-17. Furthermore, IK at 10 mg/kg attenuated CLP-induced oxidative stress by modulating levels of MDA, MPO, SOD, and GSH. Moreover, IK treatment with a dose of 10 mg/kg activated the nuclear factor erythroid 2-related factor 2-heme oxygenase-1 (Nrf2-HO-1) pathway by enhancing the protein expressions of Nrf2 and HO-1. This study demonstrates that IK could mitigate the inflammatory response and oxidative stress associated with sepsis-induced ALI, supporting IK as a promising therapeutic agent for the treatment of sepsis-associated ALI.

Guishaozichuan granules can attenuate asthma in rats via the MUC5AC/EGFR signaling pathway.

Background: Guishaozichuan (GSZC) granules are a traditional Chinese medicine formulation created by Professor Li (Chinese-Japanese Friendship Hospital, Beijing, China) we studied the effect of GSZC granules in rats suffering from asthma. Methods: Specific pathogen-free Sprague-Dawley rats were divided randomly into seven groups. Ovalbumin (OVA) and Al (OH)3 gel were used to create an asthma model. On day 1, rats were injected with OVA (10mg) and an Al(OH)3 gel suspension (100mg). One week later, rats were sensitized again. On day 15, rats were given aerosolized OVA (1%) for 30min/day for 10days. Gastric administration of OVA was 1h before nebulization. At 24h after the last stimulation, changes in airway resistance (RI) and dynamic compliance (Cdyn) in rat lungs were measured after challenge with methacholine at increasing concentrations. The contents of immunoglobulin (Ig)E, interleukin (IL)-4, IL-5, IL-13, and IL-17 in serum were measured by enzyme-linked immunosorbent assays. The percentage of eosinophils (EOS) and the white blood cell (WBC) count in bronchoalveolar lavage fluid (BALF) were counted under an optical microscope. Pathologic alterations in lung tissue were evaluated by optical microscopy, and lung injury score calculated. Expression of mucin 5AC, oligomeric mucus/gel-forming (MUC5AC) and epidermal growth factor receptor (EGFR) in lung tissue was measured by immunohistochemistry. mRNA expression of MUC5AC and EGFR in lung tissue was measured by real-time reverse transcription-quantitative polymerase chain reaction (RT-qPCR). Results: GSZC granules reduced RI markedly and improved Cdyn, decreased serum levels of IgE, IL-4, IL-5, IL-13, IL-17, %EOS and the WBC count in BALF. GSZC granules alleviated lung-tissue damage, diminished the Inflammation Score, and reduced mRNA and protein expression of MUC5AC and EGFR in lung tissue. Conclusion: GSZC granules could improve bronchial hyperresponsiveness, bronchial inflammation, and histopathologic damage in the lungs of rats suffering from asthma. This phenomenon may be related to its regulation of cytokine levels and the MUC5AC/EGFR signaling pathway.

Diacerein attenuate LPS-induced acute lung injury via inhibiting ER stress and apoptosis: Impact on the crosstalk between SphK1/S1P, TLR4/NFκB/STAT3, and NLRP3/IL-1β signaling pathways

AimsAcute lung injury (ALI) is a life-threatening clinical problem with high mortality rate and limited treatments or preventive options that represents a major challenge for clinicians. Diacerein (DIA) is a multi-target anthraquinone derivative with potent anti-inflammatory action. The aim of this study is to assess the protective effect of DIA and its potential molecular targets against lipopolysaccharide (LPS)-induced ALI in rats. Materials and methodsAdult male Sprague-Dawley rats were orally administrated DIA (50 mg/kg) for 5 consecutive days followed by a single intraperitoneal injection of LPS (5mg/kg). Key findingsDIA mitigated oxidative lung injury in LPS-challenged rats via significantly decreasing lung wet/dry (W/D) ratio, inflammatory cells infiltration, and lipid peroxidation, with concomitant elevation in enzymatic and non-enzymatic antioxidant levels in lung tissue. Likewise, DIA alleviated endoplasmic reticulum stress and markedly halted inflammation triggered by LPS challenge in pulmonary tissue by suppressing NLRP3/IL-1β and TLR4/NF-κB signaling with parallel decrease in proinflammatory cytokine levels. Interestingly, DIA down regulated Sphk1/S1P axis, reduced GSK-3β and STAT3 proteins expression, and markedly decreased caspase-3 besides increasing Bcl-2 levels in lung tissue of LPS-challenged animals. These biochemical findings was simultaneously associated with marked improvement in histological alterations of lung tissue. SignificanceThese findings verify the protective effect of DIA against LPS-induced ALI through targeting oxidative stress, endoplasmic reticulum stress, and apoptosis. Importantly, DIA halted the hyperinflammatory state triggered by LPS via multi-faceted inhibitory effect on different signaling pathways, hence DIA could potentially reduce mortality in patients with ALI.

The Protective Effect of Sulodexide on Acute Lung Injury Induced by a Murine Model of Obstructive Jaundice.

Introduction The effect of sulodexide (SLX) on obstructive jaundice- (OJ-) induced acute lung injury (ALI) in rats was examined in this study. Methods In this study, 48 rats were randomly assigned to one of six groups: sham, OJ, OJ+saline, OJ+SLX (0.5 mg/ml/d), OJ+SLX (1 mg/ml/d), and OJ+SLX (2 mg/ml/d). The pathological lung injury was assessed by histological analysis and lung injury grading. ELISA kits were used to evaluate the expression of IL-6, IL-1, TNF-α, and syndecan-1 (SDC-1) in bronchoalveolar lavage fluids (BALFs). Commercial assay kits were performed to evaluate malondialdehyde (MDA) production and catalase (CAT) activity in lung tissues. The apoptosis was assessed by TUNEL assay. The lung microvascular permeability was investigated using Evans blue leakage, lung wet/dry weight (W/D) ratio, and lung permeability index (LPI). SDC-1, claudin-5, ZO-1, and VE cadherin expression levels in lung tissues were measured using Western blot. Results The OJ-induced ALI rats showed severe lung injury. The value of IL-6, IL-1β, TNF-α, and SDC-1 in BALFs was remarkedly increased in the OJ group. MDA content, apoptotic area, apoptotic molecules, and SDC-1 level were all higher in the OJ group's lung tissues than in the sham group. CAT activity, Evans blue leakage, W/D ratio, LPI, and expression of claudin-5, ZO-1, and VE cadherin were all lower in the OJ group compared to the sham group. The degenerative alterations in lung tissue improved after 7 days of treatment with 2 mg/ml SLX. The BALFs had lower amounts of IL-6, IL-1, TNF-α, and SDC-1. The SLX therapy reduced MDA levels while restoring CAT activity. In lung tissues, SLX reduced apoptotic area and SDC-1 expression. SLX reduced lung microvascular permeability by raising the expression of Claudin-5, ZO-1, and VE-cadherin in lung tissue when compared to the OJ group. Conclusion The results suggested that SLX attenuates OJ-induced ALI in rats by protecting the pulmonary microvascular endothelial barrier.

Aerosol inhalation of Mycobacterium vaccae ameliorates airway structural remodeling in chronic asthma mouse model

Background: Airway remodeling is accepted to be a determining component within the natural history of asthma. Nebulized inhalation of Mycobacterium vaccae (M. vaccae) has a protective effect on asthmatic mice. However, little is known regarding the effect of M. vaccae on airway structural remodeling in asthmatic mice. The purpose of this study was to explore the effect and the underlying mechanism of M. vaccae aerosol inhalation on airway structural remodeling in an asthma mouse model. Methods: Chronic asthma mouse models were established by ovalbumin induction. The number of inflammatory cells in bronchoalveolar lavage fluid (BALF), pathological alterations in lung tissue, and levels of associated cytokines (IL-5, IL-13, TNF-α, and ovalbumin-specific immunoglobulin E [OVA-sIgE]) were all assessed after M. vaccae therapy. The relative expression of interleukin (IL)-1β, tumor necrosis factor-alpha (TNF-α), nuclear factor kappa B (NF-κB), and Wnt1‐induced signaling protein 1 (WISP1) mRNA were detected. Western blotting and immunohistochemistry detected the expression of Wnt/β-catenin pathway-related proteins in lung tissue. Results: M. vaccae aerosol inhalation relieved airway inflammation, airway hyper-responsiveness, and airway remodeling. M. vaccae reduced the levels of IL-5, IL-13, TNF-α, and OVA-sIgE in and downregulated the expression of IL-1β, TNF-α, NF-κB, and WISP1 mRNA in the pulmonary. In addition, M. vaccae inhibited the expression of β-catenin, WISP1, and Wnt1 protein and upregulated the expression of glycogen synthase kinase-3beta (GSK-3β). Conclusion: Nebulized inhalation of M. vaccae can reduce airway remodeling during asthma.

Chemopreventive potential of Diosmin against benzo[a]pyrene induced lung carcinogenesis in Swiss Albino mice.

Lung cancer, one of the most common cancer is a cause of concern associated with cancer-related mortality. Benzo[a]pyrene [B(a)P], a potent carcinogen as well as an environmental contaminant is reported to be found in cigarette smoke among various sources. The present study focuses on the chemopreventive potential of Diosmin against B[a]P-induced lung carcinogenesis and its possible mechanism in male Swiss Albino mice (SAM). SAM were treated orally with Diosmin (200 mg/kg b.w.) for 16 weeks and/or B[a]P (50 mg/kg b.w) for a period of 4 weeks. B[a]P treated cancerous mice showed increased peroxidation of membrane lipid as well as a decrease in the level/activity of antioxidant proteins. Cancerous mice also showed an increased level of carcinoembryonic antigen (CEA) and neuron-specific enolase (NSE). Diosmin treatment, however, leads to decreased peroxidation of lipids, increased antioxidant proteins as well decrease in the level of CEA and NSE. B[a]P-induced cancerous animals also exhibited increased expression of cyclic AMP response element-binding protein(CREB), COX2 as well as prostaglandin-E2(PGE2) while Diosmin-treated mice were found to have an ameliorative effect. Histopathological results further confirm the protective effect of Diosmin in averting B[a]P-induced pathological alterations of lung tissue. Overall, our results suggest Diosmin exerts its chemopreventive potential possibly via targeting the CREB/cyclooxygenase-2(COX-2)/PGE2 pathway thereby repressing inflammation.

Pulmonary Delivery of Hydroxychloroquine Nanostructured Lipid Carrier as a Potential Treatment of COVID-19.

Coronavirus Disease 2019 (COVID-19) is a pandemic caused by severe acute respiratory syndrome coronavirus 2. Pneumonia is considered the most severe and long-term complication of COVID-19. Among other drugs, hydroxychloroquine (HCQ) was repurposed for the management of COVID-19; however, low efficacy and cardiac toxicity of the conventional dosage form limited its use in COVID-19. Therefore, utilizing nanotechnology, a pulmonary delivery system of HCQ was investigated to overcome these limitations. HCQ was formulated in nanostructured lipid carriers (HCQ-NLCs) using the hot emulsification–ultrasonication method. Furthermore, the prepared formulation was evaluated in vitro. Moreover, the efficacy was tested in vivo in a bleomycin-induced acute lung injury mice model. Intriguingly, nanoformulations were given by the intratracheal route for 6 days. HCQ-NLCs showed a mean particle size of 277 nm and a good drug release profile. Remarkably, acute lung injury induced by bleomycin was associated with a marked elevation of inflammatory markers and histological alterations in lung tissues. Astoundingly, all these changes were significantly attenuated with HCQ-NLCs. The pulmonary delivery of HCQ-NLCs likely provided adequate targeting to lung tissues. Nevertheless, there is hope that this novel strategy will eventually lead to the improved effectiveness and diminished probability of alarming adverse drug reactions.

Molecular mechanism of betulin palliative therapy for chronic obstructive pulmonary disease (COPD) based on P2X7 receptor target of gated ion channel

BackgroundThe aim of this study was to discover the molecular mechanism of betulin palliative therapy for chronic obstructive pulmonary disease (COPD) based on the P2X7 receptor target of gated ion channel.MethodsA COPD mouse model was developed. Changes in pulmonary ventilation function, pulmonary airway and vascular remodeling indicators, inflammatory cells, and inflammatory factors were determined after betulin intervention, and the pathological alterations of lung tissues were detected. An in vitro experimental model was constructed to observe the influence of betulin at varying concentrations on the proliferation of human bronchial epidermal cell line (16-HBE) cells and changes in inflammatory factors in cell supernatant. The expression levels of key proteins in 16-HBE cells transfected with overexpressed or silenced P2X7 genes were determined through quantitative reverse transcription polymerase chain reaction (RT-qPCR) and Western blot.ResultsAfter betulin intervention, pulmonary ventilation function in the 20 mg/kg betulin and 40 mg/kg betulin groups was improved. Levels of white blood cells (WBCs), neutrophils (Ns), tumor necrosis factor (TNF), TNF-ɑ, interleukin (IL)-1β, and IL-6 in the 2 groups also decreased significantly (all P<0.05). The pathological changes in COPD mice were detected. After betulin intervention, the pathological injury of the lung was reduced, the pathological score decreased significantly, and the remodeling indicators of pulmonary airway and pulmonary vessels diminished remarkably (all P<0.05). Betulin had no effect on the proliferation of 16-HBE cells in vitro. After cigarette smoke extract (CSE) stimulation, the rate of survival for 16-HBE cells decreased significantly. After betulin treatment, the survival rate of 16-HBE cells augmented remarkably, and the levels of TNF-ɑ, IL-6, and IL-1β in cell supernatant reduced substantially (all P<0.05). 16-HBE with overexpression and knockdown of P2X7 was constructed. After being treated with betulin, the relative expression levels of messenger RNA (mRNA) of ERK, JNK, rho-associated protein kinase (ROCK), nuclear factor-κB (NF-κB), and p38 in 16-HBE cells with P2X7 overexpression or knockdown were decreased significantly (all P<0.05), but the above indicators were largely unchanged (all P>0.05).ConclusionsBetulin relieved lung pathological injury, ameliorated lung ventilation function, and diminished the level of inflammatory factors in COPD mice, playing a therapeutic role via the P2X7 signaling pathway.

Pulmonary affection of patients with Pseudoxanthoma elasticum: Long-term development and genotype-phenotype-correlation.

Pseudoxanthoma elasticum (PXE) is a rare, heritable disease caused by various, mainly recessively transmitted mutations in the ABCC6 gene. Due to calcification of soft connective tissue phenotypic hallmarks are progressive loss of vision, alternation of the skin and early onset atherosclerosis. Beside these main features patients also suffer from impaired alveolar diffusion. The present study focused on impaired lung functioning based on a large cohort of patients with PXE, its long-term development, and genotype-phenotype correlation. Retrospectively, 98 patients and 45 controls were enrolled. All patients underwent body plethysmography and carbon monoxide diffusion testing. Of 35 patients three or more body plethysmographic records were available for long-term analysis. For genotype-phenotype analysis ABCC6 genotypes were grouped as two missense, mixed, or two nonsense mutations. Patients with PXE showed significantly reduced vital capacity (p < 0.05), diffusion capacity (p < 0.01), and diffusion transfer coefficient (p < 0.05). Over a mean period of 38 months diffusion capacity (p < 0.05) and diffusion transfer coefficient (p < 0.01) dropped significantly whereas lung volumes remained unchanged. Genotype-phenotype correlation revealed no connection between gene variants and lung functioning. In conclusion, PXE is accompanied by progressive reduction of alveolar diffusion indicating progressive alterations of lung tissue. Genotype-phenotype correlation with genotypes sorted as missense and nonsense mutations do not explain impaired lung functioning.

Fine particulate matter-induced lung inflammation is mediated by pyroptosis in mice

BackgroundExposure to ambient air-borne fine particulate matter (PM2.5) increases respiratory morbidity and mortality. The mechanisms underlying PM2.5-induced adverse effects remain unclear. This study aimed to uncover the molecular mechanisms of PM2.5-induced lung toxicity using a mouse model. MethodsScanning electron microscopy and inductively coupled plasma mass spectrometry were used to examine and analyze PM2.5 morphology and element compositions, respectively. Twenty four male mice were randomly divided into three groups: control (PBS), PM2.5 (4.0 mg/kg b.w.), and PM2.5 + Z-YVAD-FMK. In the latter group, the pan-caspase inhibitor (Z-YVAD-FMK) was intraperitoneally injected into mice at a dose of 12.5 mg/kg body weight prior to intratracheal instillation of PM2.5 (4.0 mg/kg b.w.) every other day for a total of 3 times (n = 8 in each group). Bronchoalveolar lavage fluids (BALFs) were collected 24 h after the last instillation of PM2.5. Levels of total proteins (TP), lactate dehydrogenase (LDH), IL-1β and IL-18 were analyzed for biomarkers of cell injury and inflammation. Additionally, histological alterations of lung tissues were assessed by hematoxylin-eosin staining. mRNA and protein expression of Caspase1, NLRP3 and GSDMD were examined by real-time fluorescent quantitative PCR and immunohistochemical staining. ResultsExposure to PM2.5 increased levels of TP, LDH, IL-1β, IL-18 and inflammatory cell counts in lung. The mRNA and protein expression of Caspase1, NLRP3 and GSDMD were increased. Inhibition of the NALRP3/Caspase-1 signaling pathway ameliorated PM2.5-induced lung injury and inflammation, partially through suppressing pyroptosis in lung. ConclusionPM2.5 exposure induces lung injury and inflammation, which is mediated by the NALRP3/Caspase-1 signaling pathway.

Ginkgolide C attenuates lipopolysaccharide‑induced acute lung injury by inhibiting inflammation via regulating the CD40/NF‑κB signaling pathway.

Excessive lung inflammation caused by endotoxins, including lipopolysaccharide (LPS), mediates the detrimental effects of acute lung injury (ALI), as evidenced by severe alveolar epithelial cell injury. CD40, a member of the tumor necrosis factor receptor superfamily, serves as a central activator in triggering and transducing a series of severe inflammatory events during the pathological processes of ALI. Ginkgolide C (GC) is an efficient and specific inhibitor of CD40. Therefore, the present study aimed to investigate whether GC alleviated LPS-induced ALI, as well as the potential underlying mechanisms. LPS-injured wild-type and CD40 gene conditional knockout mice, and primary cultured alveolar epithelial cells isolated from these mice served as in vivo and in vitro ALI models, respectively. In the present study, histopathological assessment, polymorphonuclear neutrophil (PMN) infiltration, lung injury score, myeloperoxidase activity, wet-to-dry (W/D) weight ratio and hydroxyproline (Hyp) activity were assessed to evaluate lung injury. In addition, immunohistochemistry was performed to evaluate intracellular adhesion molecule-1, vascular cell adhesion molecule-1 and inducible nitric oxide synthase expression levels, and TNF-α, IL-1β, IL-6 ELISAs and western blotting were conducted to elucidate the signaling pathway. The results demonstrated that GC alleviated LPS-induced lung injury, as evidenced by improvements in ultrastructural characteristics and histopathological alterations of lung tissue, inhibited PMN infiltration, as well as reduced lung injury score, W/D weight ratio and hydroxyproline content. In LPS-injured alveolar epithelial cells, GC significantly reduced IκBα phosphorylation, IKKβ activity and NF-κB p65 subunit translocation via downregulating CD40, leading to a significant decrease in downstream inflammatory cytokine levels and protein expression levels. In conclusion, the results of the present study demonstrated that GC displayed a protective effect against LPS-induced ALI via inhibition of the CD40/NF-κB signaling pathway; therefore, the present study suggested that the CD40/NF-κB signaling pathway might serve as a potential therapeutic target for ALI.

The effects of dexmedetomidine administered at various times on acute lung injury in rats.

To investigate the effects of dexmedetomidine (Dex) treatment administered at various times on acute lung injury (ALI). Thirty Wistar rats were randomly divided into five groups (n = 6/group). Lipopolysaccharide (LPS) was intraperitoneally injected into the rats in the LPS, Dex1, Dex2, and Dex3 groups to induce ALI, while the control group (C) was left untreated. Rats in the Dex1 group were intraperitoneally administered with 50 µg/kg Dex 30 minutes before modeling. Rats in the Dex2 group were injected with 25 µg/kg Dex 30 minutes before modeling and two hours after. Rats in the Dex3 group received 50 µg/kg Dex two hours after modeling. The animals in the C and LPS groups were given an equal volume of saline. The wet-to-dry (W/D) weight ratio of the rats' lungs was calculated, and pathological alterations in lung tissues were observed. The concentrations of inflammation-related factors and the expression of Janus kinase 1 (JAK1), signal transducer and activator of transcription 3 (STAT3), and matrix metallopeptidase 9 (MMP9) were measured. The W/D ratio, expression of inflammatory factors, and expression of JAK1, STAT3, and MMP9 were significantly increased in the ALI rats (p < 0.05) compared with the C group. The level of anti-inflammatory factors in the Dex-treated groups was also significantly increased compared with the LPS group (p < 0.05). The concentration of anti-inflammatory factors in the Dex2 group was significantly higher than that recorded in the Dex1 and Dex3 groups (p < 0.05). Dex treatment administered at different times protects rats against LPS-induced ALI to varying degrees. The protective effects of Dex were most robust when administered both before and after LPS stimulation.

Supplementation with Tetrahydrocurcumin Enhances the Therapeutic Effects of Dexamethasone in a Murine Model of Allergic Asthma

Background: Tetrahydrocurcumin (THC) is the major active metabolite of curcumin, which is a dietary factor derived from Curcuma species. Our previous study demonstrated a significant beneficial effect of THC in mice with allergic asthma. Glucocorticosteroids (GCs) are commonly used drugs in asthma. Whether THC supplementation could promote the beneficial effects of GC therapy on asthma has not yet been reported. The current study aimed to investigate the combined efficacy of GC and THC treatment in a mouse model of allergic asthma. Methods: BALB/c mice were randomly divided into 5 groups: the control group, ovalbumin (OVA)-induced group, and OVA-induced mice treated with dietary THC only, intraperitoneal injection of dexamethasone (DEX) only, or THC combined with DEX. The nasal symptoms, histopathological alterations of lung tissues, lung cytokine production, and Th cell subsets were assessed. Results: THC or DEX had beneficial effects on nasal symptoms and pathological lung changes, and the therapeutic effects between THC and DEX treatment were comparable. Importantly, compared to the monotherapy groups (THC or DEX only), the combination of THC and DEX showed a significantly reduced nasal rubbing frequency, lower mucus hyperproduction, lower Th2 and Th17 cell numbers as well as lower related cytokine levels (IL-4, IL-5, and IL-17A). Conclusions: Supplementation with THC can enhance the therapeutic effects of DEX to alleviate airway symptoms, lung inflammation, and the Th2 response. Our findings suggest that dietary administration of THC could act as an add-on therapy for asthma treated with GCs.

BMSC-derived exosomes alleviate smoke inhalation lung injury through blockade of the HMGB1/NF-κB pathway

AimsTo investigate the role of bone marrow mesenchymal stem cell (BMSC)-derived exosomes in smoke inhalation lung injury. Main methodsIn this study, we initially isolated exosomes from BMSCs and identified them by western blot and transmission electron microscopy. BMSC-derived exosomes were then used to treat in vitro and in vivo models of smoke inhalation lung injury. Pathologic alterations in lung tissue, the levels of inflammatory factors and apoptosis-related factors, and the expression of HMGB1 and NF-κB were determined to evaluate the therapeutic effect of BMSC-derived exosomes. Key findingsWe found that BMSC-derived exosomes could alleviate the injury caused by smoke inhalation. Smoke inhalation increased the levels of inflammatory factors and apoptosis-related factors and the expression of HMGB1 and NF-κB, and these increases were reversed by BMSC-derived exosomes. HMGB1 overexpression abrogated the exosome-induced decreases in inflammatory factors, apoptosis-related factors and NF-κB. SignificanceCollectively, these results indicate that BMSC-derived exosomes can effectively alleviate smoke inhalation lung injury by inhibiting the HMGB1/NF-κB pathway, suggesting that exosome, a noncellular therapy, is a potential therapeutic strategy for inhalation lung injury.