Pulmonary pharmacology & therapeutics最新文献

{"title":"SIRT3 alleviates sepsis-induced acute lung injury by inhibiting pyroptosis via regulating the deacetylation of FoxO3a","authors":"Zheqian Wu ,&nbsp;Yong Wang ,&nbsp;Shijie Lu,&nbsp;Lili Yin,&nbsp;Lihua Dai","doi":"10.1016/j.pupt.2023.102244","DOIUrl":"10.1016/j.pupt.2023.102244","url":null,"abstract":"<div><h3>Objective</h3><p><span>This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the </span>deacetylation<span> of FoxO3a and inhibiting pyroptosis.</span></p></div><div><h3>Methods</h3><p><span>SIRT3-overexpressing and silenced BEAS-2B cells were used to evaluate the effect of SIRT3 on apoptosis in LPS-treated lung epithelial cells. FoxO3a-silenced BEAS-2B cells were also used to verify the mechanism by which SIRT3 inhibited </span>oxidative stress<span> and pyroptosis in vitro in ALI. 3-TYP was used to inhibit the deacetylation function of SIRT3 in vivo. Pyroptosis was assessed by detecting GSDMD-N and LDH efflux.</span></p></div><div><h3>Results</h3><p>In CLP-induced ALI mice, GSDMD-N and LDH levels were elevated, pyroptosis was induced. Silencing of SIRT3 exacerbated oxidative stress, NLRP3 activation and pyroptosis, and inhibited the deacetylation of FoxO3a. Overexpression of SIRT3 attenuated pyroptosis, induced deacetylation and restored the expression of FoxO3a and MnSOD. Silencing FoxO3a aggravated pyroptosis. Overexpression of SIRT3 restored the reduced FoxO3a expression and suppressed pyroptosis. 3-TYP blocked the promotion of FoxO3a by SIRT3 and the inhibitory effect of SIRT3 on pyroptosis.</p></div><div><h3>Conclusion</h3><p>The reduction of SIRT3 in sepsis caused hyperacetylation of FoxO3a, which in turn exacerbates oxidative stress and induces pyroptosis of ALI. Increasing the level of SIRT3 promotes FoxO3a through deacetylation, thereby inhibiting pyroptosis and relieving ALI.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"82 ","pages":"Article 102244"},"PeriodicalIF":3.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10281406","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The effect of bradykinin 1 receptor antagonist BI 1026706 on pulmonary inflammation after segmental lipopolysaccharide challenge in healthy smokers","authors":"Christina Gress ,&nbsp;Jens Vogel-Claussen ,&nbsp;Philipp Badorrek ,&nbsp;Meike Müller ,&nbsp;Kathrin Hohl ,&nbsp;Marilisa Konietzke ,&nbsp;Tobias Litzenburger ,&nbsp;Wolfgang Seibold ,&nbsp;Abhya Gupta ,&nbsp;Jens M. Hohlfeld","doi":"10.1016/j.pupt.2023.102246","DOIUrl":"10.1016/j.pupt.2023.102246","url":null,"abstract":"<div><h3>Background</h3><p><span><span>Bradykinin 1 receptor<span> (B1R) signalling pathways may be involved in the inflammatory </span></span>pathophysiology of </span>chronic obstructive pulmonary disease<span> (COPD). B1R signalling is induced by inflammatory stimuli or tissue injury and leads to activation and increased migration of pro-inflammatory cells. Lipopolysaccharide (LPS) lung challenge in man is an experimental method of exploring inflammation in the lung whereby interference in these pathways can help to assess pharmacologic interventions in COPD. BI 1026706, a potent B1R antagonist, was hypothesized to reduce the inflammatory activity after segmental lipopolysaccharide (LPS) challenge in humans due to decreased pulmonary cell influx.</span></p></div><div><h3>Methods</h3><p>In a monocentric, randomized, double-blind, placebo-controlled, parallel-group, phase I trial, 57 healthy, smoking subjects were treated for 28 days with either oral BI 1026706 100 mg bid or placebo. At day 21, turbo-inversion recovery magnitude magnetic resonance imaging (TIRM MRI) was performed. On the last day of treatment<span><span><span>, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 </span>endotoxin units/kg body weight) and saline control instillation in different </span>lung lobes<span>. Twenty-four hours later, TIRM MRI was performed, then BAL and biopsies were collected from the challenged segments. In BAL samples, cells were differentiated for neutrophil<span><span> numbers as the primary endpoint. Other endpoints included assessment of safety, biomarkers in BAL (e.g. interleukin-8 [IL-8], albumin and total protein), B1R expression in lung biopsies and TIRM score by MRI as a measure for the extent of </span>pulmonary oedema.</span></span></span></p></div><div><h3>Results</h3><p>After LPS, but not after saline, high numbers of inflammatory cells, predominantly neutrophils were observed in the airways. IL-8, albumin and total protein were also increased in BAL samples after LPS challenge as compared with saline control. There were no significant differences in cells or other biomarkers from BAL in volunteers treated with BI 1026706 compared with those treated with placebo. Unexpectedly, neutrophil numbers in BAL were 30% higher and MRI-derived extent of oedema was significantly higher with BI 1026706 treatment compared with placebo, 24 h after LPS challenge. Adverse events were mainly mild to moderate and not different between treatment groups.</p></div><div><h3>Conclusions</h3><p>Treatment with BI 1026706 for four weeks was safe and well-tolerated in healthy smoking subjects. BI 1026706 100 mg bid did not provide evidence for anti-inflammatory effects in the human bronchial LPS challenge model.</p></div><div><h3>Trial registration</h3><p>The study was registered on January 14, 2016 at <span>ClinicalTrials.gov</span><svg><path></path></svg> (NCT02657408).</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"82 ","pages":"Article 102246"},"PeriodicalIF":3.2,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10231708","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The impact of nintedanib and pirfenidone on lung function and survival in patients with idiopathic pulmonary fibrosis in real-life setting","authors":"Gabriela Santos ,&nbsp;André Fabiano ,&nbsp;Patrícia Caetano Mota ,&nbsp;Inês Rodrigues ,&nbsp;Diogo Carvalho ,&nbsp;Natália Melo ,&nbsp;Hélder Novais-Bastos ,&nbsp;André Terras Alexandre ,&nbsp;Conceição Souto Moura ,&nbsp;Susana Guimarães ,&nbsp;José Miguel Pereira ,&nbsp;André Carvalho ,&nbsp;António Morais","doi":"10.1016/j.pupt.2023.102261","DOIUrl":"10.1016/j.pupt.2023.102261","url":null,"abstract":"<div><h3>Background</h3><p><span>Idiopathic pulmonary fibrosis<span> (IPF) is a chronic, fibrosing interstitial pneumonia of unknown cause that is associated with radiological and/or histological features of usual interstitial pneumonia (UIP). A mean survival of 2–5 years was reported previously to the advent of antifibrotics. According to </span></span>clinical trials<span>, nintedanib<span> and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival.</span></span></p></div><div><h3>Methods</h3><p><span><span><span>A real-life retrospective and longitudinal study was conducted to assess the efficacy and tolerability of antifibrotics in IPF patients, between January 2014 and December 2020. Two groups (under nintedanib or pirfenidone) were analyzed at diagnosis through their clinical features and radiological patterns. Lung function was assessed at diagnosis (time 0) and after 6, 12 and 24 months of </span>treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with </span>immunosuppressive drugs and/or N- </span>acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®.</p></div><div><h3>Results</h3><p>A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC<span> and DLCO mean predicted percentages at 6, 12 and 24 months of treatment. The mean decline in FVC and DLCO, at 12 months, was −40.95 ± 438.26 mL and −0.626 ± 1.31 mL/min/mmHg, respectively. However, during this period, 34.2% of the patients died mostly due to acute exacerbation associated with a poorer lung function at diagnosis. Mean survival in the naïve antifibrotic cohort was significantly lower than in the antifibrotic cohort (39.9 months versus 58.2 months; p &lt; 0.005). Regarding lung function evolution and survival, we found no differences between definitive or probable UIP radiological patterns, both on patients under nintedanib and pirfenidone (p = 0.656).</span></p></div><div><h3>Conclusions</h3><p>In this real-life observational study, the positive impact of antifibrotic therapy on the IPF clinical course and on survival was corroborated. Regarding efficacy, there was no difference between patients taking nintedanib or pirfenidone. The need for an early treatment was also demonstrated, since a worse outcome is clearly associated with lower lung volumes and lower diffusing capacity at diagnosis.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102261"},"PeriodicalIF":3.2,"publicationDate":"2023-09-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41179703","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Nontuberculous mycobacterial (NTM) infections in bronchiectasis patients: A retrospective US registry cohort study","authors":"Myriam Drysdale ,&nbsp;Radmila Choate ,&nbsp;Amanda E. Brunton ,&nbsp;Simon Tiberi ,&nbsp;Iain A. Gillespie ,&nbsp;Noah Lininger ,&nbsp;Susan B. Shrimpton ,&nbsp;Mark Metersky ,&nbsp;Nicole C. Lapinel ,&nbsp;Pamela J. McShane ,&nbsp;Christopher J. Richards ,&nbsp;Colin Swenson ,&nbsp;Hema Sharma ,&nbsp;David Mannino ,&nbsp;Kevin L. Winthrop ,&nbsp;for the Bronchiectasis and NTM Research Registry Investigators","doi":"10.1016/j.pupt.2023.102260","DOIUrl":"10.1016/j.pupt.2023.102260","url":null,"abstract":"<div><h3>Rationale</h3><p>Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis<span> developing nontuberculous mycobacterial (NTM) pulmonary disease.</span></p></div><div><h3>Objectives</h3><p><span><span>To describe the epidemiology, patient management, and </span>treatment<span> outcomes of NTM infections </span></span>in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR).</p></div><div><h3>Methods</h3><p><span>This was a retrospective cohort study of patients with bronchiectasis and NTM infections enrolled with follow-up in the US BRR in 2008–2019. The study included patients with ≥1 positive NTM respiratory culture in the 24-month baseline period (baseline NTM cohort) and/or during the annual follow-up visits (incident NTM cohort). Incidence, prevalence, baseline </span>patient characteristics, treatment exposure, treatment outcomes, and respiratory clinical outcomes were described in the baseline NTM cohort, incident NTM cohort, and both cohorts combined (prevalent NTM cohort).</p></div><div><h3>Results</h3><p>Between 2008 and 2019, 37.9% (1457/3840) of patients with bronchiectasis in the US BRR met the inclusion criteria for this study and were reported to have <em>Mycobacterium avium</em> complex (MAC) and/or <span><em>Mycobacterium abscessus</em></span><span> complex (MABSC) infections. MAC prevalence increased steadily in the US BRR during 2009–2019; incidence was relatively stable, except for a peak in 2011 followed by a slow decrease. MABSC and mixed MAC/MABSC infections were rare. Most patients with bronchiectasis and NTM infections in the registry were female, White, and aged &gt;65 years. The antibiotics administered most commonly reflected current guidelines. In the prevalent cohort, 44.9% of MAC infections and 37.1% of MABSC infections remained untreated during follow-up, and MAC treatment was initiated with delay (&gt;90 days after positive NTM respiratory culture) twice as frequently as promptly (≤90 days after positive NTM respiratory culture) (68.6% vs 31.4%, respectively). The median time from diagnosis to treatment was shorter for MABSC versus MAC infections (194.0 days [interquartile range (IQR) 8.0, 380.0] vs 296.0 days [IQR 35.0, 705.0], respectively). Among patients with MAC infections who completed treatment, 27.6% were classified as cured and 29.6% as treatment failure during the annual follow-up visit window. For MABSC, these proportions were 25.0% and 28.0%, respectively.</span></p></div><div><h3>Conclusions</h3><p>A considerable proportion of MAC and MABSC infections were untreated or treated after initial delay/observation. MABSC infections were more likely to be treated and start treatment sooner than MAC infections. Further longitudinal studies are warranted to evaluate the monitor-with-delay approach and inform clinical guidelines.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102260"},"PeriodicalIF":3.2,"publicationDate":"2023-09-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41149117","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Demethyleneberberine alleviates Pseudomonas aeruginosa-induced acute pneumonia by inhibiting the AIM2 inflammasome and oxidative stress","authors":"Yanhong Han,&nbsp;Chuang Ge,&nbsp;Junmei Ye,&nbsp;Ruiyan Li,&nbsp;Yubin Zhang","doi":"10.1016/j.pupt.2023.102259","DOIUrl":"10.1016/j.pupt.2023.102259","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Background&lt;/h3&gt;&lt;p&gt;&lt;span&gt;Acute pneumonia induced by &lt;/span&gt;&lt;span&gt;&lt;em&gt;Pseudomonas aeruginosa&lt;/em&gt;&lt;/span&gt;&lt;span&gt; is characterized by massive infiltration of inflammatory cell&lt;span&gt; and the production of reactive oxygen species&lt;span&gt; (ROS), which lead to severe and transient pulmonary inflammation and acute lung injury. However, &lt;/span&gt;&lt;/span&gt;&lt;/span&gt;&lt;em&gt;P.aeruginosa&lt;/em&gt; infection is resistant to multiple antibiotics and causes high mortality in clinic, the search for alternative prophylactic and therapeutic strategies is imperative.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Purpose&lt;/h3&gt;&lt;p&gt;&lt;span&gt;&lt;span&gt;This study was aimed to investigate the anti-inflammatory and antioxidant effects of DMB, a novel derivative of berberine, and explore the role of &lt;/span&gt;AIM2&lt;span&gt; inflammasome in &lt;/span&gt;&lt;/span&gt;&lt;em&gt;P. aeruginosa&lt;/em&gt;-induced acute pneumonia.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Acute pneumonia mice were established by tracheal injection of &lt;em&gt;P. aeruginosa&lt;/em&gt;&lt;span&gt;&lt;span&gt; suspension. Pathological changes of lung tissue were observed by its appearance and H&amp;E staining. The lung coefficient ratio was measured to evaluate pulmonary edema&lt;span&gt;. Inflammatory factors were detected by qRT-PCR, western blotting and &lt;/span&gt;&lt;/span&gt;immunohistochemistry. ROS and other indicators of oxidative damage were analyzed by flow cytometry and specific kit. Proteins related to AIM2 inflammasome were detected by western blotting.&lt;/span&gt;&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Compared with the &lt;em&gt;P. aeruginosa&lt;/em&gt;&lt;span&gt;-induced group, DMB ameliorated pulmonary edema, hyperemia, and pathological damage based on its appearance and H&amp;E staining in DMB groups. First, DMB attenuated the inflammatory response induced by &lt;/span&gt;&lt;em&gt;P.aeruginosa&lt;/em&gt;. Compared with the &lt;em&gt;P. aeruginosa&lt;/em&gt;&lt;span&gt;&lt;span&gt;-induced group, the lung coefficient ratio was decreased by 31.5%, the MPO activity of lung tissue was decreased by 44.0%, the mRNA expression levels of TNF-α, IL-1β and IL-6 were decreased by 64.8%, 51.2% and 64.0% respectively, and those protein expression levels were decreased by 40.1%, 42.8% and 47.8% respectively, and the number of white blood cells, &lt;/span&gt;neutrophils&lt;span&gt; and monocytes&lt;span&gt; were decreased by 53.5%, 29.4% and 13.7% in high dose (200 mg/kg) DMB group. Second, DMB alleviates oxidative stress in the lung tissue during &lt;/span&gt;&lt;/span&gt;&lt;/span&gt;&lt;em&gt;P. aeruginosa&lt;/em&gt;-induced acute pneumonia. Compared with the &lt;em&gt;P. aeruginosa&lt;/em&gt;-induced group, the level of GSH was increased by 42.5% and MDA was decreased by 49.5% in high dose DMB group. Moreover, the western blotting results showed that DMB markedly suppressed the expression of AIM2, ASC, Cleaved caspase1 and decreased the secretion of IL-1β. Additionally, these results were also confirmed by &lt;em&gt;in vitro&lt;/em&gt; experiments using MH-S and BEAS-2B cell lines.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;Taken together, these results indicated that DMB ameliorates &lt;em&gt;P. aeruginosa&lt;/em&gt;-induced acute pneumonia through anti-inflammatory, anti","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102259"},"PeriodicalIF":3.2,"publicationDate":"2023-09-17","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41139090","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Safety and efficacy of P2X3 receptor antagonist for the treatment of refractory or unexplained chronic cough: A systematic review and meta-analysis of 11 randomized controlled trials","authors":"Alaa Ramadan ,&nbsp;Mohamed El-Samahy ,&nbsp;Amr Elrosasy ,&nbsp;Mohammed Al-Tawil ,&nbsp;Ahmed Abdelaziz ,&nbsp;Mostafa A Soliman ,&nbsp;Mohamed Abouzid","doi":"10.1016/j.pupt.2023.102252","DOIUrl":"10.1016/j.pupt.2023.102252","url":null,"abstract":"<div><h3>Background and objectives</h3><p><span>Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors<span> that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this </span></span>systematic review<span> and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs<span> in chronic cough.</span></span></p></div><div><h3>Methods</h3><p>We systematically searched PubMed, Scopus, Web of Science, and Embase to identify all relevant published studies through January 15, 2023 that assessed P2X3 antagonists in chronic cough. The protocol was registered in the PROSPERO database with ID: CRD42023422408. Efficacy outcomes were awake (daytime) cough frequency, night cough frequency, 24-h cough frequency, Cough Severity Diary, and total Leicester Cough Questionnaire score. We used the random-effect model to pool the data using RStudio and CMA software.</p></div><div><h3>Results</h3><p><span>A total of 11 randomized controlled trials comprising 1350 patients receiving a p2x3 antagonist compared to the placebo group were included in this meta-analysis. A significant decrease in 24-h cough frequency (MD = −4.99, 95% CI [−7.15 to −2.82], P &lt; 0.01), awake (daytime) cough frequency (MD = −7.18, 95% CI [−9.98 to 4.37], P &lt; 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P &lt; 0.01) exhibited between the P2X3 antagonist and placebo groups. The frequency of the night cough showed an insignificant difference between the two groups. According to the safety, drug-related adverse events, </span>dysgeusia<span><span>, hypogeusia, and </span>ageusia significantly increased between the P2X3 antagonist and placebo groups.</span></p></div><div><h3>Conclusion</h3><p>P2X3 receptor antagonists are promising drugs for treating chronic cough by significantly reducing the frequency, severity, and quality. Some potential side effects may include drug-related adverse events such as hypogeusia, ageusia, and dysgeusia.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102252"},"PeriodicalIF":3.2,"publicationDate":"2023-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10569480","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"m6A-modified miR-143-3p inhibits epithelial mesenchymal transition in bronchial epithelial cells and extracellular matrix production in lung fibroblasts by targeting Smad3","authors":"Jing Wang ,&nbsp;Qiang Jian ,&nbsp;Kun Yan ,&nbsp;Jiao Yang ,&nbsp;Liping Yan ,&nbsp;Wei Cheng","doi":"10.1016/j.pupt.2023.102251","DOIUrl":"https://doi.org/10.1016/j.pupt.2023.102251","url":null,"abstract":"<div><h3>Background</h3><p><span><span>Airway epithelial cells epithelial mesenchymal transition (EMT) and </span>lung fibroblasts </span>extracellular matrix<span><span> (ECM) production are the key steps in airway remodeling. Our previous study demonstrated that miR-143-3p has the ability to impede airway smooth muscle </span>cell proliferation and ECM deposition. However, the function of miR-143-3p in airway epithelial cells and lung fibroblasts remains unclear.</span></p></div><div><h3>Methods</h3><p><span><span>Cell viability was determined using MTT method, while cell migration was evaluated through scratch assay. EMT and </span>ECM proteins<span> were detected by western blot<span>, RT-qPCR, and ELISA. To determine the level of miR-143-3p m</span></span></span>⁶<span><span>A methylation, we employed the meRIP-qPCR assay. Additionally, the binding of miR-143-3p with Smad3 were projected by bioinformatics and validated by dual </span>luciferase reporter assays.</span></p></div><div><h3>Results</h3><p>It was discovered that the expression of miR-143-3p were lower in both asthma patients and TGF-β1-treated human bronchial epithelial 16HBE cells and human lung fibroblast HPF cells. Upregulation of miR-143-3p restrained 16HBE cell migration, and decreased EMT mesenchymal markers and increased epithelial markers. And upregulation of miR-143-3p impaired cell viability and ECM protein production in HPF cells. Mechanistically, interfering with METTL3 resulted in decreased m⁶A modification of miR-143-3p and led to lower levels of miR-143-3p. Moreover, miR-143-3p were verified to directly target and downregulate Smad3. Upregulation of Smad3 attenuated the effects of miR-143-3p on cell EMT and ECM production.</p></div><div><h3>Conclusion</h3><p>MiR-143-3p inhibits airway epithelial cell EMT as well as lung fibroblast ECM production by downregulating Smad3. Therefore, miR-143-3p may be a promising target to reduce airway remodeling in asthma.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102251"},"PeriodicalIF":3.2,"publicationDate":"2023-09-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"49856435","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Knockdown of HDAC10 inhibits POLE2-mediated DNA damage repair in NSCLC cells by increasing SP1 acetylation levels","authors":"Hua Guo ,&nbsp;Hui Ren ,&nbsp;Kun Han ,&nbsp;Jianying Li ,&nbsp;Yu Dong ,&nbsp;Xuan Zhao ,&nbsp;Chunqi Li","doi":"10.1016/j.pupt.2023.102250","DOIUrl":"10.1016/j.pupt.2023.102250","url":null,"abstract":"<div><p><span><span>HDAC10 has been reported to be associated with poor prognosis </span>in patients with non-small cell lung cancer (NSCLC), however, the regulatory role and mechanisms of HDAC10 in NSCLC have not been investigated. In this study, we found that HDAC10 was increased in NSCLC patients and cell lines. And high expression of HDAC10 is linked to poor survival in NSCLC patients. The results showed that knockdown of HDAC10 triggered DNA damage, </span><em>S</em><span><span>-phase arrest, and proliferation inhibition in A549 and H1299<span> cells. In addition, knockdown of HDAC10 promoted cell ferroptosis<span> by enhancing ROS, </span></span></span>MDA and Fe</span>²⁺<span> levels. Mechanistically, HDAC10 knockdown reduced SP1<span> expression and elevated the acetylation<span> level of SP1, which inhibited the binding of SP1 to the promoter of POLE2, resulting in reduced POLE2 expression. Overexpression of SP1 or POLE2 partially reversed the effects of HDAC10 deletion on NSCLC cell proliferation and ferroptosis. In conclusion, knockdown of HDAC10 inhibited the proliferation of NSCLC cells and promoted their ferroptosis by regulating the SP1/POLE2 axis. HDAC10 might be a promising target for the treatment of NSCLC.</span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102250"},"PeriodicalIF":3.2,"publicationDate":"2023-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10245137","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Dihydroquercetin (DHQ) ameliorates LPS-induced acute lung injury by regulating macrophage M2 polarization through IRF4/miR-132-3p/FBXW7 axis","authors":"Chen Li,&nbsp;Jianhua Liu,&nbsp;Changhong Zhang,&nbsp;Liang Cao,&nbsp;Fang Zou,&nbsp;Zhihua Zhang","doi":"10.1016/j.pupt.2023.102249","DOIUrl":"10.1016/j.pupt.2023.102249","url":null,"abstract":"<div><h3>Background</h3><p><span>Acute lung injury (ALI) is a common complication of </span>sepsis<span>. Dihydroquercetin (DHQ) has been found to attenuate lipopolysaccharide (LPS)-induced inflammation. However, the effect of DHQ on LPS-challenged ALI remains unclear.</span></p></div><div><h3>Methods</h3><p><span>Pulmonary HE and TUNEL staining<span><span> and lung wet/dry ratio were detected in LPS-treated Balb/c mice. IL-1β, IL-6 and TNF-α levels were determined utilizing ELISA assay. RAW264.7 cell </span>apoptosis<span><span> and macrophage markers (CD86, CD206) were tested using flow cytometry. TC-1 viability was analyzed by MTT assay. </span>Western blot<span><span> measured protein expression of macrophage markers. Interactions of miR-132–3p, </span>IRF4 and FBXW7 were explored utilizing </span></span></span></span>ChIP<span>, RNA pull-down and dual luciferase reporter assays.</span></p></div><div><h3>Results</h3><p>DHQ alleviated histopathological change, pulmonary edema<span><span> and apoptosis in LPS-treated mice. DHQ affected LPS-induced M2 macrophage polarization<span> and TC-1 cell injury-related indicators, such as decreased cell activity, decreased LDH levels, and increased apoptosis. </span></span>LPS inhibited IRF4 and miR-132–3p expression, activated Notch pathway and increased FBXW7 level, which were overturned by DHQ. IRF4 transcriptionally activated miR-132–3p expression. FBXW7 was a downstream target of miR-132–3p.</span></p></div><div><h3>Conclusion</h3><p>DHQ alleviated LPS-induced lung injury through promoting macrophage M2 polarization via IRF4/miR-132–3p/FBXW7 axis, which provides a new therapeutic strategy for ALI.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102249"},"PeriodicalIF":3.2,"publicationDate":"2023-08-28","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10199282","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Relative bioavailability of budesonide/glycopyrrolate/formoterol fumarate triple therapy delivered using next generation propellants with low global warming potential","authors":"Magnus Aurivillius ,&nbsp;Artur Bednarczyk ,&nbsp;Marek Kokot ,&nbsp;Jonathan Madriaga ,&nbsp;Jie Mei ,&nbsp;Kathryn Collison ,&nbsp;Raulin Surujbally ,&nbsp;James Archbell ,&nbsp;Vidya Joshi ,&nbsp;Michael Gillen","doi":"10.1016/j.pupt.2023.102245","DOIUrl":"10.1016/j.pupt.2023.102245","url":null,"abstract":"&lt;div&gt;&lt;h3&gt;Introduction&lt;/h3&gt;&lt;p&gt;The climate crisis poses an immediate threat to human health and well-being, demanding urgent adaptions across sectors, including healthcare. The development of pressurized metered dose inhalers (MDIs) with greater sensitivity to the climate emergency using novel propellants with lower global warming potentials (GWPs), but comparable pharmacokinetic (PK) parameters to currently marketed MDIs, is a vital step toward reducing the impact of healthcare for respiratory disorders on climate change. This study evaluated the relative bioavailabilities of the individual components of a fixed-dose combination of budesonide/glycopyrrolate/formoterol fumarate (BGF) 160/9/4.8 μg per actuation between three different propellant formulations.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Methods&lt;/h3&gt;&lt;p&gt;Healthy male participants (aged 18–60 years) were randomized into a single-blind, three-period, single-dose, single-center, crossover study (NCT04600505). The PK and safety and tolerability profiles of BGF MDI formulated with two novel propellants with low GWP (hydrofluoroolefin-1234ze [HFO]; hydrofluorocarbon-152a [HFC]) were compared with BGF MDI formulated with the propellant used in the currently marketed reference product (hydrofluoroalkane-134a [HFA]). The study included a screening period, three treatment periods (with 3- to 7-day washout periods between each dose), and a follow-up. The primary PK parameters assessed were maximum observed plasma concentration (C&lt;sub&gt;max&lt;/sub&gt;), area under the plasma concentration curve (AUC) from time zero extrapolated to infinity (AUC&lt;sub&gt;inf&lt;/sub&gt;), and AUC from time zero to the time of the last quantifiable analyte concentration (AUC&lt;sub&gt;last&lt;/sub&gt;). The study was not powered to statistically demonstrate bioequivalence.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Results&lt;/h3&gt;&lt;p&gt;Forty-seven participants completed the study, and 24 participants were evaluable for PK assessments. Systemic exposure, based on geometric mean ratios (90% confidence interval), to each BGF component from the test propellants delivered in a standard MDI was comparable with the reference propellant for AUC&lt;sub&gt;last&lt;/sub&gt; (HFO vs. HFA: budesonide, 107.30 [94.53, 121.90]; glycopyrrolate, 106.10 [86.18, 130.60]; formoterol, 98.13 [86.44, 111.40]; HFC vs. HFA: budesonide, 98.80 [84.59, 115.40]; glycopyrrolate, 99.71 [80.84, 123.00]; formoterol, 107.00 [88.82, 128.90]); AUC&lt;sub&gt;inf&lt;/sub&gt; (where evaluable) and C&lt;sub&gt;max&lt;/sub&gt; followed the same trend. There were no serious adverse events or adverse events leading to treatment discontinuation. No new safety signals were observed.&lt;/p&gt;&lt;/div&gt;&lt;div&gt;&lt;h3&gt;Conclusions&lt;/h3&gt;&lt;p&gt;Systemic BGF component exposure was similar for both test propellants (HFO and HFC) compared with the HFA reference propellant, with an acceptable safety profile in the studied population. Therefore, both novel low GWP propellants show strong potential as candidates for development of MDIs with greater sensitivity to the climate crisis, a vital step toward amelioratin","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":"83 ","pages":"Article 102245"},"PeriodicalIF":3.2,"publicationDate":"2023-08-20","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10226716","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}