Pulmonary pharmacology & therapeutics最新文献

{"title":"May a different kinetic mode explain the high efficacy/safety profile of inhaled budesonide?","authors":"Ralph Brattsand ,&nbsp;Olof Selroos","doi":"10.1016/j.pupt.2022.102167","DOIUrl":"10.1016/j.pupt.2022.102167","url":null,"abstract":"<div><p>The claimed functional basis for ICSs in asthma and COPD is airway selectivity, attained by inhaling a potent, lipophilic compound with long local dissolution/absorption time. The development has been empirically based, resulting in five widely used ICSs. Among them, budesonide (BUD) deviates by being less lipophilic, leading to a more rapid systemic uptake with plasma peaks with some systemic anti-inflammatory activity. By this, BUD fits less well into the current pharmacological dogma of optimal ICS profile.</p><p>In this review we compared the physicochemical, pharmacological and clinical properties of BUD, fluticasone propionate (FP) and fluticasone furoate (FF), representing different levels of lipophilicity, airway and systemic kinetics, focusing on their long-acting β2-agonist (LABA) combinations, in line with current GINA and GOLD recommendations. We are aware of the differences between formoterol (FORM) and the not rapid acting LABAs such as e.g. salmeterol and vilanterol but our comparisons are based on currently available combination products. A beclomethasone dipropionate (BDP)/FORM combination is also commented upon.</p><p>Based on clinical comparisons in asthma and COPD, we conclude that the BUD/formoterol (BUD/FORM) combination is as effective and safe as the FP and FF combinations, and is in some cases even better as it can be used as “maintenance plus reliever therapy” (MART) in asthma and as maintenance in COPD. This is difficult to explain by current views of required ICS's/LABAs pharmacokinetic profiles.</p><p>We propose that BUD achieves its efficacy by a combination of airway and systemic activity. The airway activity is dominating. The systemic activity contributes by plasma peaks, which are high enough for supportive anti-inflammatory actions at the blood and bone marrow levels but not sufficiently long to trigger a similar level of systemic adverse effects. This may be due to BUD's capacity to exploit a systemic differentiation mechanism as programmed for cortisol's various actions. This differentiation prospect can be reached only for an ICS with short plasma half-life. Here we present an alternative mode for an ICS to reach combined efficacy and safety, based on a poorly investigated and exploited physiological mechanism. A preference of this mode is broader versatility, due to that its straighter dose-response should allow a better adaptation to disease fluctuations, and that its rapid activity enables use as “anti-inflammatory reliever”.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S109455392200058X/pdfft?md5=f7938a46167cf44d9cae838602820799&pid=1-s2.0-S109455392200058X-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360053","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Assessment of extrafine beclomethasone/formoterol for the treatment of chronic obstructive pulmonary disease: A non-interventional study in a Bulgarian population","authors":"Vladimir A. Hodzhev ,&nbsp;Andrey N. Kenderov ,&nbsp;Yavor Y. Ivanov ,&nbsp;Diana P. Gospodinova-Vulkova ,&nbsp;Krasimir Kalinov","doi":"10.1016/j.pupt.2022.102169","DOIUrl":"10.1016/j.pupt.2022.102169","url":null,"abstract":"<div><h3>Background</h3><p>The beneficial effects of application of a fixed dose beclomethasone dipropionate (BDP) and formoterol fumarate (F) for the treatment of severe chronic obstructive disease (COPD) has been amply proven in well controlled clinical trials. Whether this also holds for real-world conditions and in such a heterogeneous patient population as is encountered in Bulgaria remained to be investigated.</p></div><div><h3>Methods</h3><p>In an observational, non-interventional study, 441 Bulgarian patients with severe COPD who were enrolled at 36 sites across the country received extrafine BDP/FF-combination therapy using the NEXThaler® DPI or the Foster® pMDI over a period of 16 weeks. At visits at the beginning, after 4 weeks and at the end of the study, alterations in lung function parameters FEV₁ and FVC, disease symptoms, changes in CAT score, and patient distribution in GOLD 2017 categories A through D were assessed.</p></div><div><h3>Results</h3><p>A large share of the Bulgarian patients with severe COPD suffered from serious comorbidities, received additional medication, and about 2/3 were former or current smokers. Extrafine BDP/FF caused an increase in mean FEV₁, FVC, a decrease of health impact as assessed by the CAT score, and a considerable shift of the share of category C and D patients towards A and B. In addition, the percentage of patients that were free of symptoms impacting everyday life such as fatigue and shortness of breath at rest increased throughout the study. A comparison of both application devices indicated that the NEXThaler® was superior in terms of lung functional aspects, as these parameters displayed a constant improvement over the observation period, whereas they plateaued at week 4 when using the pMDI.</p></div><div><h3>Conclusions</h3><p>The therapeutic benefits of extrafine BDP/FF known from clinical trials could also be observed in a real-world setting, even in such a heterogenous patient population as the Bulgarian. The NEXThaler® appeared to be highly efficient in this setting, opening a new choice for the lung specialist and the patient to select the one device considered most suitable and practical.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000608/pdfft?md5=8a3a9a12308aad893fdd17871bb2061f&pid=1-s2.0-S1094553922000608-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10710715","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Statins’ still controversial role in pulmonary fibrosis: What does the evidence show?","authors":"Dimitrios Andreikos ,&nbsp;Theodoros Karampitsakos ,&nbsp;Argyrios Tzouvelekis ,&nbsp;Grigoris Stratakos","doi":"10.1016/j.pupt.2022.102168","DOIUrl":"10.1016/j.pupt.2022.102168","url":null,"abstract":"<div><p>Pulmonary fibrosis<span> (PF) represents the end stage of a broad range of interstitial lung diseases<span> (ILDs). Statins are among the compounds which have been implicated in drug-induced ILD development. However, recent studies (both in vitro and in vivo) have provided evidence that statins may exert anti-inflammatory and anti-fibrotic effects potentially offering benefits to patients with PF.</span></span></p><p><span><span>Several protective molecular mechanisms including the suppression of mevalonic acid<span> pathway, the inhibition of NADPH oxidase activation in macrophages and the inhibition of several profibrotic mediators have been proposed to explain the observed in vivo decrease of the </span></span>oxidative stress in the lung and the preservation of lung function </span>in patients.</p><p>Earlier clinical studies relating statins with drug-induced ILD development are contradicted by increasing new data showing the beneficial effects of statins in clinical outcomes in ILD patients who receive statins for concomitant cardiovascular indications.</p><p>Future research may further elucidate the wide spectrum of pathways of IPF pathogenesis, and genetic heterogeneity<span>, identifying clinically applicable biomarkers and specific endotypes thus recognizing in which patients statins could confer benefit and in which they might cause detrimental effects.</span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10360316","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":"Pyrroloquinoline quinone (PQQ) improves pulmonary hypertension by regulating mitochondrial and metabolic functions","authors":"Mohammad Shafiq ,&nbsp;Zahid Rasool Lone ,&nbsp;Pragya Bharati ,&nbsp;Satyapriya Mahapatra ,&nbsp;Prashant Rai ,&nbsp;Nilesh Khandelwal ,&nbsp;Anil Nilkanth Gaikwad ,&nbsp;Kumaravelu Jagavelu ,&nbsp;Kashif Hanif","doi":"10.1016/j.pupt.2022.102156","DOIUrl":"10.1016/j.pupt.2022.102156","url":null,"abstract":"<div><p><span><span>Excessive proliferation of pulmonary artery smooth muscle cells (PASMCs) and </span>endothelial cells<span> (PAECs), inflammation, as well as mitochondrial and metabolic dysregulation, contributes to the development of pulmonary hypertension (PH). </span></span>Pyrroloquinoline quinone<span> (PQQ), a potent natural antioxidant<span><span> with anti-diabetic, neuroprotective<span><span>, and cardioprotective properties, is known to promote mitochondrial biogenesis. However, its effect on </span>cellular proliferation, </span></span>apoptosis<span> resistance, mitochondrial and metabolic alterations associated with PH remains unexplored. The current study was designed to investigate the effect of PQQ in the treatment<span><span> of PH. Human pulmonary artery smooth muscle cells (HPASMCs), endothelial cells (PAECs), and primary cultured cardiomyocytes were subjected to </span>hypoxia<span><span><span> to induce PH-like phenotype. Furthermore, Sprague Dawley (SD) rats injected with monocrotaline (MCT) (60 mg/kg, SC, once) progressively developed pulmonary hypertension. PQQ treatment (2 mg/kg, PO, for 35 days) attenuated cellular proliferation and promoted apoptosis via a mitochondrial-dependent pathway. Furthermore, PQQ treatment in HPASMCs prevented mitochondrial and metabolic dysfunctions, improved mitochondrial bioenergetics while preserving respiratory complexes, and reduced insulin resistance. In addition, PQQ treatment (preventive and curative) significantly attenuated the increase in </span>right ventricle pressure and hypertrophy as well as reduced </span>endothelial dysfunction<span> and pulmonary artery remodeling in MCT-treated rats. PQQ also prevented cardiac fibrosis and improved cardiac functions as well as reduced inflammation in MCT-treated rats. Altogether, the above findings demonstrate that PQQ can attenuate mitochondrial as well as metabolic abnormalities in PASMCs and also prevent the development of PH in MCT treated rats; hence PQQ may act as a potential therapeutic agent for the treatment of PH.</span></span></span></span></span></span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40645688","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":"Efficacy and safety of sequential combination therapy for pulmonary arterial hypertension: A meta-analysis of Randomized-Controlled Trials","authors":"Zhen Tan ,&nbsp;Pan-yun Wu ,&nbsp;Teng-teng Zhu,&nbsp;Wen Su,&nbsp;Zhen-fei Fang","doi":"10.1016/j.pupt.2022.102144","DOIUrl":"10.1016/j.pupt.2022.102144","url":null,"abstract":"<div><h3>Background</h3><p>Previous meta-analyses of pulmonary arterial hypertension (PAH) combination therapy pooled sequential and initial combination together, which might threaten their authenticity and clinical significance for the difference between two strategies.</p></div><div><h3>Methods</h3><p>PubMed, Embase, and the Cochrane Library were searched for randomized controlled trials (RCTs) that compared sequential combination therapy (SCT) with background therapy (BT) in PAH patients. Raw data were extracted to calculate risk ratio (RR) or weighted mean difference (WMD) for predefined efficacy and safety outcomes. Mantel-Haenszel fixed or random effects model was used based on heterogeneity.</p></div><div><h3>Results</h3><p>17 RCTs involving 4343 patients (97.2% of patients with WHO-FC II-III) were included. SCT decreased clinical worsening (RR 0.66, 95% CI 0.58 to 0.76), nonfatal clinical worsening (RR 0.61, 95% CI 0.52 to 0.71), functional class (decrease of 28% in the portion of patients with WHO-FC worsening and increase of 33% in the portion of patients with WHO-FC improvement), and increased 6-min walk distance (WMD 17.68 m, 95% CI 10.16 to 25.20), but didn't reduce mortality, lung transplantation, admission to hospital, and treatment escalation compared with BT. Although any adverse event and serious adverse event were similar between SCT and BT, SCT increased all-cause treatment discontinuation (RR 1.49, 95% CI 1.30 to 1.71) and drug-related treatment discontinuation (RR 2.30, 95% CI 1.86 to 2.84) with higher incidence of headache, flushing, nausea, diarrhoea and jaw pain.</p></div><div><h3>Conclusions</h3><p>For WHO-FC II-III PAH patients who have established BT, our study reinforced the recommendation of SCT to improve clinical worsening, functional status, and exercise capacity, although with higher incidence of side-effects and withdrawal.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S1094553922000359/pdfft?md5=f43bfa0987f95b4f26c56249d3c82169&pid=1-s2.0-S1094553922000359-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40595068","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of intrapleural fibrinolytic therapy and dosing strategies used for complicated pleural effusions","authors":"Laura Baumgartner ,&nbsp;Eric Huang ,&nbsp;Deborah Sherman","doi":"10.1016/j.pupt.2022.102146","DOIUrl":"10.1016/j.pupt.2022.102146","url":null,"abstract":"<div><h3>Objectives</h3><p>Compare the use of Tissue Plasminogen Activator<span><span> (t-PA) and t-PA + Dornase (DNase) for the management of complicated </span>pleural effusions, and to determine if a dose-response relationship exists for t-PA.</span></p></div><div><h3>Methods</h3><p><span>Retrospective cohort study that examined all adult patients at a large academic medical center who received intrapleural t-PA or t-PA + DNase for the management of a complicated pleural effusions. Outcomes were success of therapy [defined as avoidance of secondary interventions (i.e. </span>VATSD or thoracotomy)], chest tube output pre- and post-administration, radiographic findings, t-PA dose and frequency, and bleeding complications.</p></div><div><h3>Results</h3><p>Thirty-five patients were enrolled: 25 received t-PA and 10 received t-PA + DNase. Successful pharmacologic treatment occurred in 88% of patients receiving t-PA and 100% of patients receiving t-PA + DNase (p = 0.54). In the t-PA group, chest tube output increased from 75 ml/12 h to 538 ml/12 h after administration of t-PA (p = 0.001), and from 103 ml/12 h to 502 ml/12 h (p = 0.001) in the t-PA + DNase group. Radiographic improvement occurred in 84% of t-PA patients and 90% of t-PA + DNase patients (p = 0.99). In the t-PA group, a successful response occurred in 92% of patients receiving a cumulative dose of ≤10 mg (n = 13) and 83% of patients receiving a cumulative dose of &gt;10 mg (n = 12), p = 0.43. Patients who received a single t-PA dose compared to those who received multiple doses also had similar success rates (p = 1). There was one instance of bleeding following drug administration.</p></div><div><h3>Conclusion</h3><p>Both t-PA and t-PA + DNase were highly effective for reducing a patient's need for surgical intervention. Higher cumulative doses or more frequency administrations did not appear to provide additional benefit.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40617861","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":"Real-world safety profiles of pirfenidone and nintedanib in idiopathic pulmonary fibrosis patients","authors":"Dorine Fournier ,&nbsp;Stéphane Jouneau ,&nbsp;Guillaume Bouzillé ,&nbsp;Elisabeth Polard ,&nbsp;Marie-Noëlle Osmont ,&nbsp;Lucie-Marie Scailteux","doi":"10.1016/j.pupt.2022.102149","DOIUrl":"10.1016/j.pupt.2022.102149","url":null,"abstract":"<div><h3>Introduction</h3><p><span><span><span>While pirfenidone and </span>nintedanib have greatly influenced the </span>treatment of </span>idiopathic pulmonary fibrosis<span> (IPF), both drugs<span> have significant early adverse drug reactions<span> (ADRs) and almost nothing is known of their rare and delayed ADRs. We collected and analyzed pirfenidone- or nintedanib-related ADRs identified in a French rare lung disease center, recorded their profiles and identified potential safety signals.</span></span></span></p></div><div><h3>Methods</h3><p>We analyzed the medical records of IPF patients treated with pirfenidone or nintedanib between January 2011 and January 2020 at the Rennes University Hospital to estimate the incidence of serious and non-serious ADRs cases due to each drug and the incidence of ADRs involving the cardiovascular, hepatobiliary, gastro-intestinal, dermatological, and metabolic/nutritional systems.</p></div><div><h3>Results</h3><p>The 176 patients included 115 (65%) initially treated with pirfenidone and 61 (35%) given nintedanib. ADRs occurred in 78.3% of those given pirfenidone and in 70.5% of those given nintedanib. The incidence of first serious ADRs cases was about 33 per 100 person-years (100 PY) for both drugs; first non-serious pirfenidone ADRs cases were 102 per 100 PY and 130 per 100 PY for nintedanib. The incidence involving each organ system were quite similar, except for the gastro-intestinal and skin disorders. Cardiovascular disorders occurred in about 10 cases per 100 PY in both pirfenidone and nintedanib patients.</p></div><div><h3>Discussion</h3><p>Most ADRs were consistent with the expected antifibrotic drug safety profiles. As arterial and venous thromboembolic events are rare, it is important to assess the risk associated with using antifibrotics by a dedicated pharmacoepidemiological study.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40595069","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":"Dexmedetomidine reduces IL-4 and IgE expression through downregulation of theTLR4/NF-κB signaling pathway to alleviate airway hyperresponsiveness in OVA mice","authors":"Juan Zhi ,&nbsp;Qirui Duan ,&nbsp;Qian yu Wang ,&nbsp;Xiyu Du ,&nbsp;Dong Yang","doi":"10.1016/j.pupt.2022.102147","DOIUrl":"10.1016/j.pupt.2022.102147","url":null,"abstract":"<div><h3>Background</h3><p><span><span><span><span>Airway hyperresponsiveness (AHR) is a clinical manifestation of airflow limitation due to abnormal tracheal and bronchial sensitivity and is the main basis for the diagnosis of asthma. Patients with AHR are at high risk of perioperative tracheal and </span>bronchospasm, which can lead to </span>hypoxaemia and </span>haemodynamic instability and, in severe cases, to a life-threatening ‘silent lung’. It is therefore important to reduce the incidence or intensity of AHR episodes in the </span>perioperative period. The inflammatory response is key to the development and progression of AHR.</p></div><div><h3>Hypothesis/purpose</h3><p><span>Based on the modulatory role of dexmedetomidine<span> (DEX) in the inflammatory response, we hypothesised that dexmedetomidine (DEX) attenuates inflammatory properties by inhibiting the toll-like receptor 4 (TLR4)/nuclear factor (NF-κB) signalling pathway and can reduce the respiratory parameters of </span></span>mechanical ventilation in ovalbumin-induced allergic airway hyperresponsiveness.</p></div><div><h3>Study design</h3><p>BABL/C mice were divided into control and OVA groups (ovalbumin-induced allergy. Ten mice in all OVA models were randomly selected for in vivo invasive lung function monitoring to analyse airway resistance<span><span> parameters and demonstrate successful model establishment. The remaining OVA mice were treated with dexmedetomidine 25 μg/kg for 5 days (OVA + DEX group) or dexmedetomidine 25 μg/kg + yohimbine 1 mg/kg for 5 days (OVA + DEX + yohimbine). After </span>treatment<span>, bronchoalveolar lavage fluid<span> (BAL) and peripheral blood (ELISA) and lung tissue (H&amp;E and PAS) were collected for analysis of inflammatory factors, and lung tissue was verified by PCR for genes and proteins that do correlate with inflammatory mediators.</span></span></span></p></div><div><h3>Results</h3><p>All airway resistance parameters were increased in OVA mice by invasive lung function monitoring. Proximal airway resistance (parameter Rn) and total respiratory resistance (parameter Rrs) were attenuated after dexmedetomidine intervention treatment. Dexmedetomidine reduced total inflammatory cell<span> count and inflammatory infiltration of lung tissue in BALF and down-regulated IL-4 and IgE levels in BALF and peripheral blood, as shown by Giemsa, H&amp;E, PAS staining and ELISA; this mechanism of action was found to be related to the TLR4/NFκB pathway, but not to TLR4/NFκB, as measured by PCR.</span></p></div><div><h3>Conclusion</h3><p>Dexmedetomidine reduces hyperresponsiveness and airway inflammatory responses. This mechanism of action may be related to the TLR4/NFκB signalling pathway. Overall conclusions are presented in.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"40527847","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":"Inhaled delivery of a lipid nanoparticle encapsulated messenger RNA encoding a ciliary protein for the treatment of primary ciliary dyskinesia","authors":"Caroline J. Woo ,&nbsp;Ayed Allawzi ,&nbsp;Nicholas Clark ,&nbsp;Neha Kaushal ,&nbsp;Tim Efthymiou ,&nbsp;Maike Thamsen ,&nbsp;Jane Nguyen ,&nbsp;Richard Wooster ,&nbsp;James C. Sullivan","doi":"10.1016/j.pupt.2022.102134","DOIUrl":"https://doi.org/10.1016/j.pupt.2022.102134","url":null,"abstract":"<div><p><span><span>Primary ciliary dyskinesia<span> (PCD) is a respiratory disease<span> caused by dysfunction of the cilia with currently no approved treatments. This predominantly </span></span></span>autosomal recessive disease is caused by mutations in any one of over 50 genes involved in cilia function; </span>DNAI1<span><span> is one of the more frequently mutated genes, accounting for approximately 5–10% of diagnosed PCD cases. A codon-optimized mRNA encoding DNAI1 and encapsulated in a lipid nanoparticle<span> (LNP) was administered to mice via aerosolized inhalation resulting in the expression human DNAI1 in the multiciliated cells of the pseudostratified columnar epithelia<span>. The spatial localization of DNAI1 expression in the bronchioles<span> indicate that delivery of the DNAI1 mRNA transpires the lower airways. In a PCD disease model, exposure to the LNP-encapsulated DNAI1 mRNA resulted in increased ciliary beat frequency using high speed videomicroscopy showing the potential for an mRNA therapeutic to correct cilia function </span></span></span></span>in patients with PCD due to DNAI1 mutations.</span></p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"136799208","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":"Strongyloides venezuelensis-derived venestatin ameliorates asthma pathogenesis by suppressing receptor for advanced glycation end-products-mediated signaling","authors":"Daigo Tsubokawa ,&nbsp;Masashi Satoh","doi":"10.1016/j.pupt.2022.102148","DOIUrl":"10.1016/j.pupt.2022.102148","url":null,"abstract":"<div><h3>Introduction</h3><p>EF-hand Ca²⁺<span>-binding proteins such as S100 protein family members are recognized by the receptor for advanced glycation end-products (RAGE) and are involved in the pathogenesis of asthma/allergic airway inflammation (AAI). Venestatin, an EF-hand Ca</span>²⁺<span>-binding protein, which is secreted by the parasitic helminth </span><span><em>Strongyloides</em><em> venezuelensis</em></span><span><span>, binds with RAGE and suppresses RAGE-mediated inflammatory responses after parasite invasion. In this study, we evaluated the effect of venestatin on pathogenesis in a </span>house dust mite (HDM) murine model of asthma/AAI.</span></p></div><div><h3>Methods</h3><p><span>Mice were intranasally treated with HDM, HDM with recombinant venestatin, or HDM with synthetic peptides, which were designed based on the EF-hand Ca</span>²⁺-binding domain of venestatin. Pro-inflammatory responses in the lungs of mice were assessed.</p></div><div><h3>Results</h3><p><span>HDM treatment induced inflammatory </span>cell infiltration, phosphorylation of the mitogen-activated protein kinase and inhibitor κB, and production of the cytokines tumor necrosis factor-α and interleukin-5 in the lungs. Co-administration of recombinant venestatin with HDM suppressed these pro-inflammatory responses. Treatment with synthetic peptides reduced inflammatory cell infiltration in a RAGE-dependent manner.</p></div><div><h3>Conclusion</h3><p>The EF-hand domain of venestatin may have potential therapeutic benefits in asthma.</p></div>","PeriodicalId":20799,"journal":{"name":"Pulmonary pharmacology & therapeutics","volume":null,"pages":null},"PeriodicalIF":3.2,"publicationDate":"2022-08-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10401079","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}