Treatment Of Pulmonary Disease Research Articles

Mitochondrial dynamics in pulmonary disease: Implications for the potential therapeutics.

Mitochondria are dynamic organelles that continuously undergo fusion/fission to maintain normal cell physiological activities and energy metabolism. When mitochondrial dynamics is unbalanced, mitochondrial homeostasis is broken, thus damaging mitochondrial function. Accumulating evidence demonstrates that impairment in mitochondrial dynamics leads to lung tissue injury and pulmonary disease progression in a variety of disease models, including inflammatory responses, apoptosis, and barrier breakdown, and that the role of mitochondrial dynamics varies among pulmonary diseases. These findings suggest that modulation of mitochondrial dynamics may be considered as a valid therapeutic strategy in pulmonary diseases. In this review, we discuss the current evidence on the role of mitochondrial dynamics in pulmonary diseases, with a particular focus on its underlying mechanisms in the development of acute lung injury (ALI)/acute respiratory distress syndrome (ARDS), chronic obstructive pulmonary disease (COPD), asthma, pulmonary fibrosis (PF), pulmonary arterial hypertension (PAH), lung cancer and bronchopulmonary dysplasia (BPD), and outline effective drugs targeting mitochondrial dynamics-related proteins, highlighting the great potential of targeting mitochondrial dynamics in the treatment of pulmonary disease.

Assessment of nonadherence to inhalation therapy in asthma and chronic obstructive pulmonary disease in Bulgaria

Introduction: Treatment for asthma and chronic obstructive pulmonary disease (COPD) is compromised, quality of life is negatively impacted, and significant financial losses result from nonadherence to the prescribed therapy. Aim: To assess the nonadherence to inhaled therapy in patients with asthma and COPD in Bulgaria. Materials and methods: A survey was conducted in 4020 asthma or COPD patients. Demographic data was collected, and a questionnaire was completed for assessing the adherence to inhalation therapy (using the Test of Adherence to Inhalers®, TAI). Results: We found some level of nonadherence to the therapy in 77.2% of the patients. Factors such as sex, education, and smoking did not influence the adherence. There were regional differences in the diagnoses of asthma and COPD concerning intentional or unintentional nonadherence. Erratic and intentional nonadherence occurred more frequently with longer disease duration. When pMDIs were used as opposed to DPI devices, unintentional nonadherence to treatment was more frequent. Using pMDI instead of DPI was associated with a higher likelihood of observing erratic or intentional nonadherence in some regions of the country. There was a positive link between erratic nonadherence to therapy and an intentional or unintentional nonadherences to it. Conclusions: The rate of nonadherence to inhalation therapy for asthma and COPD in Bulgaria is very high and vary for the different regions. The TAI questionnaire allows a quick assessment and definition of the basic types of nonadherence. Correcting the causes of non-adherence to therapy reduces the frequency of exacerbations, improves quality of life, and prolongs the life expectancy of patients with asthma or COPD.

Efficacy and cerebral mechanisms of acupuncture for chronic obstructive pulmonary disease: study protocol for a multicenter, randomized controlled neuroimaging trial.

Although acupuncture is recommended by chronic obstructive pulmonary disease (COPD) treatment guidelines owing to its effects on dyspnea, the underlying neurobiological mechanisms of these effects remain unclear. This study aims to evaluate the efficacy of acupuncture in patients with stable COPD and explore the possible involvement of specific brain regions. This is a prospective, multicenter, single-blind, randomized controlled trial. A total of 90 participants will be recruited from three centers and will be randomly assigned in a 1:1 ratio to undergo acupuncture at acupoints on the disease-affected meridian (DAM) or non-acupoints on the non-affected meridian (NAM), in addition to routine pharmacological treatments. All participants will undergo 30 min of acupuncture three times a week for 8 weeks and will be followed up for 12 months. The primary outcome will be the severity of dyspnea, as measured using the Borg Dyspnea Scale and a visual analog scale at rest and after exercise. The secondary outcomes will include the multidimensional profile of dyspnea using Dyspnea-12, the modified Medical Research Council Dyspnea Scale, and the COPD assessment test; quality of life assessments using St George's Respiratory Questionnaire and the Hospital Anxiety and Depression Scale; and additional measurements of exacerbation frequency, pulmonary function, and the 6-min walking distance. Magnetic resonance imaging (MRI) will be performed before and after exercise to explore the potential neurobiological mechanisms of exertional dyspnea. Anxiety and depression will be measured and analyzed for their correlation with the activation of specific brain areas involved in dyspnea. This randomized controlled trial aims to use a multidimensional evaluation of the efficacy of acupuncture in relieving dyspnea in patients with COPD in terms of emotion and quality of life and explore the neurobiological mechanisms underlying the effects of acupuncture on dyspnea from an imaging perspective. It is expected to provide strong evidence to support the use of acupuncture in relieving dyspnea in patients with COPD and those with aother diseases involving dyspnea. Additionally, it provides novel insights into the central mechanisms of acupuncture intervention and dyspnea. Chinese Clinical Trial Registry (https://www.chictr.org.cn/): ChiCTR2300071725.

Bronchoscopic treatments of chronic obstructive pulmonary disease (COPD): a narrative review

Bronchoscopic treatments of chronic obstructive pulmonary disease (COPD): a narrative review

Inhibition of SARS-CoV-2 Nsp9 ssDNA-Binding Activity and Cytotoxic Effects on H838, H1975, and A549 Human Non-Small Cell Lung Cancer Cells: Exploring the Potential of Nepenthes miranda Leaf Extract for Pulmonary Disease Treatment.

Carnivorous pitcher plants from the genus Nepenthes are renowned for their ethnobotanical uses. This research explores the therapeutic potential of Nepenthes miranda leaf extract against nonstructural protein 9 (Nsp9) of SARS-CoV-2 and in treating human non-small cell lung carcinoma (NSCLC) cell lines. Nsp9, essential for SARS-CoV-2 RNA replication, was expressed and purified, and its interaction with ssDNA was assessed. Initial tests with myricetin and oridonin, known for targeting ssDNA-binding proteins and Nsp9, respectively, did not inhibit the ssDNA-binding activity of Nsp9. Subsequent screenings of various N. miranda extracts identified those using acetone, methanol, and ethanol as particularly effective in disrupting Nsp9's ssDNA-binding activity, as evidenced by electrophoretic mobility shift assays. Molecular docking studies highlighted stigmast-5-en-3-ol and lupenone, major components in the leaf extract of N. miranda, as potential inhibitors. The cytotoxic properties of N. miranda leaf extract were examined across NSCLC lines H1975, A549, and H838, focusing on cell survival, apoptosis, and migration. Results showed a dose-dependent cytotoxic effect in the following order: H1975 > A549 > H838 cells, indicating specificity. Enhanced anticancer effects were observed when the extract was combined with afatinib, suggesting synergistic interactions. Flow cytometry indicated that N. miranda leaf extract could induce G2 cell cycle arrest in H1975 cells, potentially inhibiting cancer cell proliferation. Gas chromatography-mass spectrometry (GC-MS) enabled the tentative identification of the 19 most abundant compounds in the leaf extract of N. miranda. These outcomes underscore the dual utility of N. miranda leaf extract in potentially managing SARS-CoV-2 infection through Nsp9 inhibition and offering anticancer benefits against lung carcinoma. These results significantly broaden the potential medical applications of N. miranda leaf extract, suggesting its use not only in traditional remedies but also as a prospective treatment for pulmonary diseases. Overall, our findings position the leaf extract of N. miranda as a promising source of natural compounds for anticancer therapeutics and antiviral therapies, warranting further investigation into its molecular mechanisms and potential clinical applications.

Comparison of efficacies of different treatments for nontuberculous mycobacterial pulmonary disease in Anhui Province, China.

Although nontuberculous mycobacterial (NTM) infection is a common cause of pulmonary disease worldwide, few studies have focused on epidemiological and therapeutic factors related to NTM cases in Anhui Province, China. This retrospective study aimed to identify aetiological and clinical factors, and treatment outcomes of patients with NTM pulmonary disease (NTMPD) in Anhui. Retrospective clinical data obtained from medical records of NTMPD patients seeking care at Anhui Chest Hospital from July 2019 to June 2022 were analyzed. Treatment outcomes were compared between two patient groups: one receiving a standardised NTM treatment regimen and the other receiving precision treatment regimens. Genotypic analysis of 672 clinical NTMPD-associated isolates revealed that most were Mycobacterium intracellulare, while drug-susceptibility test results demonstrated diverse antibiotic resistance profiles for these isolates. Cough was the most common symptom for 101 NTMPD patients. After patients of both groups received treatment, symptoms improved, sputum culture conversion was observed for some patients, imaging findings stabilised; however, no statistically significant intergroup differences in treatment outcomes were found. In this study, M. intracellulare was the predominant NTM species identified in isolates obtained from NTMPD patients. Drug resistance profiles of our patient isolates were complex, highlighting the need for administration of timely, more effective, standardised treatments for patients with NTMPD in Anhui Province, China.

Urban-rural and socio-economic differences in inhaled corticosteroid treatment for chronic obstructive pulmonary disease: A nationwide register-based cross-sectional study

BackgroundUrban-rural disparities within chronic obstructive pulmonary disease (COPD) have been documented in USA, but not in Europe. Inhaled corticosteroids (ICS) are widely used in COPD despite strict recommendations. We aimed to investigate urban-rural and socioeconomic differences in ICS treatment for COPD. MethodsA Danish nationwide register-based cross-sectional study. All patients alive on the December 31, 2018 with a J44 ICD-10 diagnosis code (COPD) were included (99,057 patients). Daily average ICS dose was calculated from the accumulated ICS use during 2018 based on redeemed prescriptions. Patients were divided into groups: No ICS, low dose ICS, medium dose ICS, high dose ICS. A multinomial logistic regression model including educational level, co-habitation status, age, and sex was performed with “No ICS” as reference group. ResultsCompared to capital municipalities, living in other municipality types was associated with an increased probability of receiving medium and high dose ICS treatment, and increasing odds ratios (ORs) were seen with increasing ICS dose (medium dose ICS: ORs between 1.31 (95 % confidence interval (CI) 1.24–1.38) and 1.35 (95%CI 1.28–1.41), high dose ICS: ORs between 1.73 (95%CI 1.59–1.88) and 1.80 (95%CI 1.68–1.92)). Patients had increased probability of receiving ICS treatment if they were female, were co-habiting, or had completed only primary education. ConclusionPatients with a hospital-registered COPD diagnosis in non-capital municipalities receive more ICS, and in higher doses, compared to patients in capital municipalities. This is the first study to confirm that such urban-rural differences exist in Europe, and further research on this area is warranted.

Nebulized Inhalation of Peptide-Modified DNA Origami To Alleviate Acute Lung Injury.

Acute lung injury (ALI) is a severe inflammatory lung disease, with high mortality rates. Early intervention by reactive oxygen species (ROS) scavengers could reduce ROS accumulation, break the inflammation expansion chain in alveolar macrophages (AMs), and avoid irreversible damage to alveolar epithelial and endothelial cells. Here, we reported cell-penetrating R9 peptide-modified triangular DNA origami nanostructures (tDONs-R9) as a novel nebulizable drug that could reach the deep alveolar regions and exhibit an enhanced uptake preference of macrophages. tDONs-R9 suppressed the expression of pro-inflammatory cytokines and drove polarization toward the anti-inflammatory M2 phenotype in macrophages. In the LPS-induced ALI mouse model, treatment with nebulized tDONs-R9 alleviated the overwhelming ROS, pro-inflammatory cytokines, and neutrophil infiltration in the lungs. Our study demonstrates that tDONs-R9 has the potential for ALI treatment, and the programmable DNA origami nanostructures provide a new drug delivery platform for pulmonary disease treatment with high delivery efficiency and biosecurity.

Purinergic regulation of pulmonary vascular tone.

Purinergic signaling is a crucial determinant in the regulation of pulmonary vascular physiology and presents a promising avenue for addressing lung diseases. This intricate signaling system encompasses two primary receptor classes: P1 and P2 receptors. P1 receptors selectively bind adenosine, while P2 receptors exhibit an affinity for ATP, ADP, UTP, and UDP. Functionally, P1 receptors are associated with vasodilation, while P2 receptors mediate vasoconstriction, particularly in basally relaxed vessels, through modulation of intracellular Ca2+ levels. The P2X subtype receptors facilitate extracellular Ca2+ influx, while the P2Y subtype receptors are linked to endoplasmic reticulum Ca2+ release. Notably, the primary receptor responsible for ATP-induced vasoconstriction is P2X1, with α,β-meATP and UDP being identified as potent vasoconstrictor agonists. Interestingly, ATP has been shown to induce endothelium-dependent vasodilation in pre-constricted vessels, associated with nitric oxide (NO) release. In the context of P1 receptors, adenosine stimulation of pulmonary vessels has been unequivocally demonstrated to induce vasodilation, with a clear dependency on the A2B receptor, as evidenced in studies involving guinea pigs and rats. Importantly, evidence strongly suggests that this vasodilation occurs independently of endothelium-mediated mechanisms. Furthermore, studies have revealed variations in the expression of purinergic receptors across different vessel sizes, with reports indicating notably higher expression of P2Y1, P2Y2, and P2Y4 receptors in small pulmonary arteries. While the existing evidence in this area is still emerging, it underscores the urgent need for a comprehensive examination of the specific characteristics of purinergic signaling in the regulation of pulmonary vascular tone, particularly focusing on the disparities observed across different intrapulmonary vessel sizes. Consequently, this review aims to meticulously explore the current evidence regarding the role of purinergic signaling in pulmonary vascular tone regulation, with a specific emphasis on the variations observed in intrapulmonary vessel sizes. This endeavor is critical, as purinergic signaling holds substantial promise in the modulation of vascular tone and in the proactive prevention and treatment of pulmonary vascular diseases.

In silico investigation of inhalation condition impacts on hygroscopic growth and deposition of salbutamol sulphate in human airways

The objective of this study is to explore the transport, size growth, and deposition of Salbutamol Sulphate (SS) using Computational Fluid Dynamics (CFD). A CT-based realistic model of human airways from the oral cavity to the 5th generation of the lung was utilized as the computational domain. Four Test Cases (TC) with varying temperature and relative humidity (RH) under two inspiratory waveforms were considered to completely evaluate the impact of inhalation conditions on particle growth. Salbutamol Sulphate (SS) is a β2-adrenergic agonist and has been extensively used for asthma treatment. A monodispersed distribution of SS particles with an initial diameter of 167 nm was considered at the mouth inlet based on pharmaceutical data. Results indicated that inhalation of saturated/supersaturated air (RH>100%) leads to significant hygroscopic growth of SS particles with a factor of 10. In addition, the deposition efficiency of SS particles under the Quick and Deep (QD) inhalation profile was enhanced as the flow temperature and humidity increased. However, the implementation of Slow and Deep (SD) inspiratory waveform revealed that the same particle size growth is achieved in the respiratory system with lower deposition efficiency in the mouth-throat (less than 3%) and tracheobronchial airway (less than 2.18%). For the escaped particles form the right lung, in the SD waveform under TC 3, the maximum particle size distribution was for 600 nm particles with 25% probability. In the left lung, 30% of the particles were increased up to 950 nm in size. For the QD waveform in TC 3 and TC4, the most frequent particles were 800 nm with 36% probability. This holds practical significance in the context of deep lung delivery for asthmatic patients with enhanced deposition efficiency and large particle size. The findings of the present study can contribute to the development of targeted drug delivery strategies for the treatment of pulmonary diseases using hygroscopic dry powder formulations.

Network Meta-analysis of traditional Chinese medicine injections in treatment of chronic pulmonary heart disease

Based on the network Meta-analysis, the efficacy and safety of different traditional Chinese medicine(TCM) injections in the treatment of chronic pulmonary heart disease(CPHD) were systematically evaluated. CNKI, Wanfang, VIP, SinoMed, Web of Science, PubMed, EMbase, and Cochrane Library were searched to collect randomized controlled trial(RCT) of TCM injection in the treatment of CPHD from inception to October 1, 2023. The quality of the included studies was evaluated by the bias risk assessment tool recommended by the Cochrane systematic evaluation manual version 5.3. Stata 17.0 and RevMan 5.4 software were used for statistical analysis of the data. Finally, 103 RCTs were included, involving 9 332 patients and 13 kinds of TCM injections. Network Meta-analysis yielded the following results.(1)In terms of improving the total clinical effective rate, the top three intervention measures in SUCRA ranking are Shuxuetong Injection + conventional western medicine>Ligustrazine Injection + conventional western medicine>Xinmailong Injection + conventional western medicine.(2)In terms of reducing pulmonary artery pressure, the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Ligustrazine Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(3)In terms of improving left ventricular ejection fraction(LVEF), the top three intervention measures in SUCRA ranking are Xinmailong Injection + conventional western medicine>Danhong Injection + conventional western medicine>Ginkgo Damo Injection + conventional western medicine.(4) In terms of reducing brain natriuretic peptide(BNP), the top three intervention measures in SUCRA ranking are Xinmailong Injection + conventional wes-tern medicine>Ginkgo Damo Injection + conventional western medicine>Danhong Injection + conventional western medicine.(5) In terms of increasing arterial oxygen partial pressure(PaO_2) and reducing arterial carbon dioxide partial pressure(PaCO_2), the top three intervention measures in SUCRA ranking are Shenxiong Glucose Injection + conventional western medicine>Shenmai Injection + conventional western medicine>Shenfu Injection + conventional western medicine.(6) In terms of improving arterial oxygen saturation(SaO_2), the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Xinmailong Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(7) In terms of increasing the percentage of forced expiratory volume in the first second(FEV_1%), the top three intervention measures in SUCRA ranking are Shenfu Injection + conventional western medicine>Tanshinone Sodium Ⅱ_A Sulfonate Injection + conventional western medicine>Shenmai Injection + conventional western medicine.(8) In terms of increasing the proportion of forced expiratory volume to forced vital capacity in the first second(FEV_1/FVC), the top three intervention measures in SUCRA ranking are Salvia Miltiorrhiza Ligustrazine Injection + conventional western medicine>Shuxuetong Injection + conventional western medicine>Danhong Injection + conventional western medicine.(9) In terms of safety, neither the experimental group nor the control group experienced any serious adverse drug reactions during the treatment period. In summary, combining TCM injection with conventional western medicine treatment can improve the comprehensive efficacy of treating CPHD, reduce pulmonary artery pressure, and improve cardiopulmonary function and arterial blood gas levels. However, due to the limitations of the quality and quantity of research methodology included, the above conclusions need to be further validated by more well-designed and high-quality RCT.

RAPID ENDOGENOUS PRODUCTION OF ENDOTHELIN-1 REVEALED BY AN ENDOTHELIN NEUTRALIZING ANTIBODY IN A SERIES OF EXPERIMENTAL AND MODELING STUDIES

Objective: The endothelin pathway is implicated in driving pathophysiological changes leading to pulmonary and systemic hypertension, chronic kidney disease and heart failure. Small molecule antagonists that selectively blocked endothelin A receptors (ETA) as well as non-selective ETA and endothelin B receptor (ETB) antagonists were successfully developed for the treatment of these vascular diseases. However, the treatment-related adverse events, such as fluid retention and edema, significantly limit the utility of this class of therapeutics, especially in the heart failure patients. Design and method: A monoclonal antibody that selectively neutralizes endothelin-1 (ET-1) may offer an attractive alternative therapeutic approach that remedies ETA-mediated vasoconstriction without impacting desirable ET-3/ETB mediated fluid regulation. A selective ET-1/2 neutralizing antibody, S69glC21 was discovered and optimized through protein engineering to 80 pM and 30 pM binding affinities to ET-1 and ET-2, respectively. Results: When administered into rats exogenously infused with ET-1, S69glC21 prevented blood pressure increase. In a hypoxia-induced pulmonary hypertension rat model, S69glC21 reduced pulmonary pressure. Compared to atrasentan, a selective small molecule ETA antagonist, S69glC21 had a distinct pharmacodynamic (PD) effect characterized by initial complete inhibition followed by a delayed rise of pulmonary pressure as the hypoxia condition persisted. To further dissect these findings, S69glC21 pharmacokinetics (PK) and circulating ET-1 target engagement (TE) analysis were performed. In the S69glC21 treated rats, antibody bound ET-1 was shown to accumulate relative to baseline plasma levels at all dose levels. In the 30 mpk group, the antibody bound ET-1 accumulated nearly 40,000-fold above the baseline plasma level of 2.25 ± 0.87 pg/mL indicating a rapid production rate of ET-1. Conclusions: Thus, PK/PD modeling reveals significant druggability challenges for the development of a highly effective, commercially viable ET-1 selective neutralizing antibody for the treatment of cardiovascular, pulmonary, and/or renal diseases.

RNA modifications in pulmonary diseases.

Threatening public health, pulmonary disease (PD) encompasses diverse lung injuries like chronic obstructive PD, pulmonary fibrosis, asthma, pulmonary infections due to pathogen invasion, and fatal lung cancer. The crucial involvement of RNA epigenetic modifications in PD pathogenesis is underscored by robust evidence. These modifications not only shape cell fates but also finely modulate the expression of genes linked to disease progression, suggesting their utility as biomarkers and targets for therapeutic strategies. The critical RNA modifications implicated in PDs are summarized in this review, including N6-methylation of adenosine, N1-methylation of adenosine, 5-methylcytosine, pseudouridine (5-ribosyl uracil), 7-methylguanosine, and adenosine to inosine editing, along with relevant regulatory mechanisms. By shedding light on the pathology of PDs, these summaries could spur the identification of new biomarkers and therapeutic strategies, ultimately paving the way for early PD diagnosis and treatment innovation.

Pharmacokinetic Models for Inhaled Fluticasone Propionate and Salmeterol Xinafoate to Quantify Batch-to-Batch Variability.

Advair Diskus is an essential treatment for asthma and chronic obstructive pulmonary disease. It is a dry powder inhaler with a combination of fluticasone propionate (FP) and salmeterol xinafoate (SX). However, the pharmacokinetics (PK) batch-to-batch variability of the reference-listed drug (RLD) hindered its generic product development. This work developed the PK models for inhaled FP and SX that could represent potential batch variability. Two batches each of the reference and the test product (R1, R2, T1, T2) of Advair Diskus (100μg FP/50μg SX inhalation) were administered to 60 healthy subjects in a 4-period, 4-sequence crossover study. The failure of the bioequivalence (BE) between R1 and R2 confirmed the high between-batch variability of the RLD. Non-linear mixed effect modeling was used to estimate the population mean PK parameters for each batch. For FP, a 2-compartment model with a sequential dual zero-order absorption best described the PK profile. For SX, a 2-compartment model with a first-order absorption model best fit the data. Both models were able to capture the plasma concentration, the maximum concentration, and the total exposure (AUCinf) adequately for each batch, which could be used to simulate the BE study in the future. In vitro properties were also measured for each batch, and the batch with a higher fraction of the fine particle (diameter < 1µm, < 2µm) had a higher AUCinf. This positive correlation for both FP and SX could potentially assist the batch selection for the PK BE study.

Non-pharmacological Treatment for Nontuberculous Mycobacterial Pulmonary Disease.

Nontuberculous mycobacterial pulmonary disease (NTM-PD) arises from the exposure of susceptible hosts to a diverse group of environmental mycobacteria. The emphasis on non-pharmacological strategies is motivated by widespread presence of nontuberculous mycobacteria (NTM) in various environments and the inconsistent success rates of pharmacological treatments. Modifiable factors contributing to NTM-PD development include impaired airway clearance, low body mass index, gastroesophageal reflux disease, and exposure to NTM habitats. This suggests that lifestyle and environmental modifications could affect disease development and progression. The review highlights several modalities that can modify the risk factors. Airway clearance techniques, informed by the "gel-on-brush" model of the bronchial epithelium, aims at enhancing mucociliary clearance and have potential in alleviating symptoms and potentially improving lung function. The impact of nutritional status is also examined, with a lower body mass index linked to an increased risk and progression of NTM-PD, indicating the importance of targeted nutritional support. Additionally, the theoretical and epidemiological links between gastroesophageal reflux disease and NTM-PD advocates for careful management of reflux episodes. Understanding the risk of NTM transmission through environmental exposure to contaminated water and soil is also crucial. Strategies to mitigate this risk, including effective water management and minimizing soil contact, are presented as vital preventive measures. In conclusion, the review supports the inclusion of non-pharmacological treatments within a comprehensive NTM-PD management strategy, alongside conventional pharmacological therapies. This integrated approach seeks to improve the overall understanding and handling of NTM-PD.

Anti-inflammatory effect of Anadenanthera colubrina var. cebil (Griseb.) Altschul in experimental elastase-induced pulmonary emphysema in rats

Ethnopharmacological relevanceMedicinal plants have shown promise in the search for new treatments of pulmonary emphysema. Anadenanthera colubrina, a species native to the Caatinga biome in northeastern Brazil, is widely recognized and traditionally employed in the treatment of pulmonary diseases. Many studies corroborate popular knowledge about the medicinal applications of A. colubrina, which has demonstrated a remarkable variety of pharmacological properties, however, its anti-inflammatory and antioxidant properties are highlighted. Aim of the studyThe objective of this study was to investigate the anti-inflammatory potential of the crude hydroethanolic extract of A. colubrina var. cebil (Griseb.) Altschul on pulmonary emphysema in rats as well as to determine its potential genotoxic and cytotoxic effects using the micronucleus assay. Materials and methodsThe stem bark of the plant was collected in Pimenteiras-PI and sample was extracted by maceration using 70% ethanol. A portion of the extract underwent phytochemical analyses using TLC and HPLC. In this study, 8-week-old, male Wistar rats weighing approximately ±200 g was utilized following approval by local ethics committee for animal experimentation (No. 718/2022). Pulmonary emphysema was induced through orotracheal instillation of elastase, and treatment with A. colubrina extract or dexamethasone (positive control) concomitantly during induction. Twenty-eight days after the initiation of the protocol, plasma was used for cytokine measurement. Bronchoalveolar lavage (BAL) was used for leukocyte count. After euthanasia, lung samples were processed for histological analysis and quantification of oxidative stress markers. The micronucleus test was performed by evaluating the number of polychromatic erythrocytes (PCE) with micronuclei (MNPCE) to verify potential genotoxic effects of A. colubrina. A differential count of PCE and normochromatic erythrocytes (NCE) was performed to verify the potential cytotoxicity of the extract. Parametric data were subjected to normality analysis and subsequently to analysis of variance and Tukey or Dunnett post-test, non-parametric data were treated using the Kruskal-Wallis test with Dunn's post-test for unpaired samples. P value < 0.05 were considered significant. ResultsThe A. colubrina extract did not show a significant increase in the number of MNPCE (p > 0.05), demonstrating low genotoxicity. No changes were observed in the PCE/NCE ratio of treated animals, compared with the vehicle, suggesting low cytotoxic potential of the extract. A significant reduction (p < 0.05) in neutrophilic inflammation was observed in the lungs of rats treated with the extract, evidenced by presence of these cells in both the tissue and BAL. The extract also demonstrated pulmonary antioxidant activity, with a significant decrease (p < 0.05) in myeloperoxidase, malondialdehyde, and nitrite levels. TNFα, IL-1β, and IL-6 levels, as well as alveolar damage, were significantly reduced in animals treated with A. colubrina extract. Phytochemical analyses identified the presence of phenolic compounds and hydrolysable tannins in the A. colubrina extract. ConclusionsThe findings of this study highlights the safety of the hydroethanolic extract of Anadenanthera colubrina, and demonstrates its potential as a therapeutic approach in the treatment of emphysema. The observed properties of this medicinal plant provide an optimistic outlook in the development of therapies for the treatment of pulmonary emphysema.

Simultaneous quantitation of 15 bioactive components in Yupingfeng granules by LC-MS/MS.

Yupingfeng granules (YPFG) is commonly used in the treatment of immunological diseases, inflammations, and pulmonary diseases. Several studies have found that chromones, flavones, and saponins were the major bioactive compounds of YPFG. However, few studies have reported accurate quantification methods of these compounds. This study aimed to establish a simple and rapid method by using liquid chromatography-tandem mass spectrometry (LC-MS/MS) to determine 15 bioactive compounds in YPFG. The experimental parameters including extraction methods, extraction solvents, extraction time, solid-liquid ratio, and LC-MS/MS condition were optimized. The linearity, precision, repeatability, stability, and recovery of the established method were evaluated. The contents of 15 bioactive compounds in seven batches of YPFG samples were analyzed by the established method and the results were compared with the values determined by HPLC. The optimal extraction condition was to extract 0.1 g of YPFG by ultrasound with 50 mL 50% ethanol for 30 min. A Waters ACQUITY UPLCBEH C18 column using the 0.1% formic acid water solution and acetonitrile as mobile phase with a gradient elution was applied to the chromatographic separation. The linearity, precision, repeatability, stability, and recovery of the method were within acceptable ranges. Compared with HPLC analysis methods in Chinese Pharmacopoeia and literature, the established method was faster, simpler, more accurate, and more reliable. The method of simultaneous determination of 15 components in YPFG by LC-MS might provide a basis for the study of the bioactive compounds and the improvement of the quality standard of YPFG.

Exosomes: efficient macrophage-related immunomodulators in chronic lung diseases.

Macrophages, the predominant immune cells in the lungs, play a pivotal role in maintaining the delicate balance of the pulmonary immune microenvironment. However, in chronic inflammatory lung diseases and lung cancer, macrophage phenotypes undergo distinct transitions, with M1-predominant macrophages promoting inflammatory damage and M2-predominant macrophages fostering cancer progression. Exosomes, as critical mediators of intercellular signaling and substance exchange, participate in pathological reshaping of macrophages during development of pulmonary inflammatory diseases and lung cancer. Specifically, in inflammatory lung diseases, exosomes promote the pro-inflammatory phenotype of macrophages, suppress the anti-inflammatory phenotype, and subsequently, exosomes released by reshaped macrophages further exacerbate inflammatory damage. In cancer, exosomes promote pro-tumor tumor-associated macrophages (TAMs); inhibit anti-tumor TAMs; and exosomes released by TAMs further enhance tumor proliferation, metastasis, and resistance to chemotherapy. Simultaneously, exosomes exhibit a dual role, holding the potential to transmit immune-modulating molecules and load therapeutic agents and offering prospects for restoring immune dysregulation in macrophages during chronic inflammatory lung diseases and lung cancer. In chronic inflammatory lung diseases, this is manifested by exosomes reshaping anti-inflammatory macrophages, inhibiting pro-inflammatory macrophages, and alleviating inflammatory damage post-reshaping. In lung cancer, exosomes reshape anti-tumor macrophages, inhibit pro-tumor macrophages, and reshaped macrophages secrete exosomes that suppress lung cancer development. Looking ahead, efficient and targeted exosome-based therapies may emerge as a promising direction for treatment of pulmonary diseases.

Exosomes derived from induced cardiopulmonary progenitor cells alleviate acute lung injury in mice.

Cardiopulmonary progenitor cells (CPPs) constitute a minor subpopulation of cells that are commonly associated with heart and lung morphogenesis during embryonic development but completely subside after birth. This fact offers the possibility for the treatment of pulmonary heart disease (PHD), in which the lung and heart are both damaged. A reliable source of CPPs is urgently needed. In this study, we reprogrammed human cardiac fibroblasts (HCFs) into CPP-like cells (or induced CPPs, iCPPs) and evaluated the therapeutic potential of iCPP-derived exosomes for acute lung injury (ALI). iCPPs were created in passage 3 primary HCFs by overexpressing GLI1, WNT2, ISL1 and TBX5 (GWIT). Exosomes were isolated from the culture medium of passage 6-8 GWIT-iCPPs. A mouse ALI model was established by intratracheal instillation of LPS. Four hours after LPS instillation, ALI mice were treated with GWIT-iCPP-derived exosomes (5 × 109, 5 × 1010 particles/mL) via intratracheal instillation. We showed that GWIT-iCPPs could differentiate into cell lineages, such as cardiomyocyte-like cells, endothelial cells, smooth muscle cells and alveolar epithelial cells, in vitro. Transcription analysis revealed that GWIT-iCPPs have potential for heart and lung development. Intratracheal instillation of iCPP-derived exosomes dose-dependently alleviated LPS-induced ALI in mice by attenuating lung inflammation, promoting endothelial function and restoring capillary endothelial cells and the epithelial cells barrier. This study provides a potential new method for the prevention and treatment of cardiopulmonary injury, especially lung injury, and provides a new cell model for drug screening.

Adjuvant surgical resection for nontuberculous mycobacterial pulmonary disease: Effectiveness and complications.

Standard antibiotic treatment for nontuberculous mycobacteria pulmonary disease (NTMPD) has unsatisfactory success rates. Pulmonary resection is considered adjunctive therapy for patients with refractory disease or severe complications, but surgical indications and extent of resection remain unclear. We present surgical treatment outcomes for NTMPD and analyzes risk factors for unfavorable outcomes. We conducted a retrospective investigation of medical records for patients diagnosed with NTMPD who underwent surgical treatment at Asan Medical Center between 2007 and 2021. We analyzed clinical data including microbiological and surgical outcomes. A total of 71 NTMPD patients underwent thoracic surgery. Negative conversion of acid-fast bacillus (AFB) culture following pulmonary resection was observed in 51 (73.9%) patients. In terms of long-term outcomes, negative conversion was sustained in 38 cases (55.1%). Mortality occurred in 7 patients who underwent pulmonary resections for NTMPD. Statistically significant associations with factors for recurrence or non-negative conversion of AFB culture were found in older age (odds ratio [OR] =1.093, 95% confidence interval [CI]: 1.029-1.161, P = 0.004), male sex (OR = 0.251, 95% CI: 0.071-0.892, P = 0.033), and extensive NTMPD lesions involving three lobes or more (OR = 5.362, 95% CI: 1.315-21.857, P = 0.019). Interstitial lung disease (OR = 13.111, 95% CI: 1.554-110.585, P = 0.018) and pneumonectomy (OR = 19.667, 95% CI: 2.017-191.797, P = 0.018) were statistically significant risk factors for postoperative mortality. Pulmonary resection can be an effective adjuvant treatment option for NTMPD patients, with post-operative antibiotic treatment as the primary treatment. Careful patient selection is crucial, considering the associated risk factors and resectability due to complications and recurrence.