Pulmonary pharmacology & therapeutics最新文献

The initial alterations of chronic obstructive pulmonary disease (COPD) involve the small airways. Small airway disease (SAD) is related to lung hyperinflation and air trapping. Several lung function tests may detect the presence of SAD, namely forced mid-expiratory flows, residual volume (RV), RV/total lung capacity (TLC) ratio, functional residual capacity, airway resistances obtained with body-plethysmography and oscillometry, and the single-breath nitrogen washout test. Additionally, high-resolution computed tomography can detect SAD. In addition to SAD, COPD is related to cardiovascular disease (CVD) such as heart failure, peripheral vascular disease, and ischemic heart disease. No studies have assessed the relationship between CVD, COPD, and SAD. Therefore, the main objective of the Assessing the Relationship between Cardiovascular and small Airway Disease and Acute events in COPD (ARCADIA) study is to assess the risk of CVD in COPD patients according to SAD in a real-life setting. The correlation between CVD, mortality, and acute exacerbation of COPD (AECOPD) is also evaluated.

ARCADIA is a 52-week prospective, multicentre, pilot, observational, cohort study conducted in ≥22 pulmonary centres in Italy and that enrols ≥500 COPD patients, regardless of disease severity (protocol registration: ISRCTN49392136). SAD is evaluated at baseline, after that CVD, mortality, and AECOPD are recorded at 6 and 12 months. Bayesian inference is used to quantify the risk and correlation of the investigated outcomes in COPD patients according to SAD.

The ARCADIA study provides relevant findings in the daily clinical management of COPD patients.

Background

The drug combination elexacaftor-tezacaftor-ivacaftor (ETI) proved highly effective in the improvement of the respiratory symptoms, the percentage of predicted forced expiratory volume in 1 s (FEV1), and to reduce rates of pulmonary exacerbations in people with cystic fibrosis (CF) with at least one F508del mutation.

The objectives of the study were to evaluate the impact of ETI on the daily treatment burden due to patient decision and the evolution of lung function parameters at 6 months of treatment in real life.

Methods

A single-center observational study was realized including adult patients starting ETI therapy from March 10, 2020 to April 5, 2022. Clinical characteristics were collected at initiation (T0) and at 6 months (T6) of treatment. Outcome measures included names and number of chronic daily medications, respectively lung function parameters: FEV1, forced vital capacity (FVC), FEV1/FVC ratio, peak expiratory flow (PEF), forced expiratory flow at 25–75% of FVC (FEF25-75), β‐angle and FEF50/PEF ratio.

Results

Sixty-five patients were included with a mean age of 29.4 ± 8.5 years old, 48% of them F508del homozygous previously treated by lumacaftor-ivacaftor. At T6, the median number of daily medications decreased from 13 [2-24] to 9 [1-19] (p < 0.001). All the studied functional respiratory parameters were improved: FEV1 +18%, FVC +14%, FEF25-75% + 18% (all p < 0.001), as well the airflow obstruction: FEV1/FVC +6%, FEF50/PEF by 0.1 ± 0.1 and β‐angle by 10° ± 13° (all p ≤ 0.007).

Conclusion

ETI therapy can reduce the daily treatment burden in real-life at 6 months of treatment, increase a large number of lung function parameters and improve airflow obstruction.

Hypoxic pulmonary hypertension (HPH) is a devastating disease worldwide; however, effective therapeutic drugs are lacking. This study investigated the effects and underlying mechanisms of LCZ696 treatment on hypoxia-induced pulmonary hypertension. Male Sprague-Dawley (SD) rats were kept in a hypobaric chamber with an oxygen concentration of 5% for 4 weeks. Rats were treated with either LCZ696 (18 mg/kg, 36 mg/kg, and 72 mg/kg) or sildenafil. The mean pulmonary artery pressure (mPAP), right ventricle hypertrophy index (RVHI), and lung system index were measured. Hematoxylin-eosin (HE) staining, Masson staining, and immunofluorescence staining were used for histological analysis. Enzyme linked immunosorbent assay (ELISA) kits were used to determine the concentrations of inflammatory and hypoxia-related factors. Western blotting was used to examine the expression of apoptotic and PI3K/AKT signaling pathway proteins in rat lung tissue. Hypoxia increased mPAP, RVHI, and lung system index and induced pulmonary vascular remodeling, pulmonary arteriomyosis, and pulmonary artery fibrosis. LCZ696 treatment reduced the increase in mPAP, RVHI, and the lung system index and ameliorated the induced pathological changes. Hypoxia upregulated expression of NF-kB, TNF-α, IL-6, HIF-1α, and Vascular endothelial growth factor (VEGF), decreased the ratio of Bax/Bcl-2, and activated the PI3K/AKT signaling pathway in lung tissue, and these effects were partially reversed by treatment with LCZ696. These results demonstrated that LCZ696 can ameliorate hypoxia-induced HPH by suppressing apoptosis, inhibiting the inflammatory response, and inhibiting the PI3K/AKT signaling pathway. It provides a reference for clinical rational drug use and lays a foundation for the study of HPH therapeutic drugs.

Objective

This study mainly analyzes the mechanism of SIRT3 alleviating sepsis-induced acute lung injury (ALI) by regulating the deacetylation of FoxO3a and inhibiting pyroptosis.

Methods

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 oxidative stress 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.

Results

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.

Conclusion

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.

Background

Bradykinin 1 receptor (B1R) signalling pathways may be involved in the inflammatory pathophysiology of chronic obstructive pulmonary disease (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.

Methods

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, pre-challenge bronchoalveolar lavage fluid (BAL) and biopsies were sampled, followed by segmental LPS challenge (40 endotoxin units/kg body weight) and saline control instillation in different lung lobes. 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 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 pulmonary oedema.

Results

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.

Conclusions

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.

Trial registration

The study was registered on January 14, 2016 at ClinicalTrials.gov (NCT02657408).

Background

Idiopathic pulmonary fibrosis (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 clinical trials, nintedanib and pirfenidone induce a significant delay in functional decline, with a favorable impact on survival.

Methods

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 treatment. We also compared this antifibrotic cohort with an older naïve antifibrotic cohort, mainly treated with immunosuppressive drugs and/or N- acetylcysteine. Survival was analyzed and prognostic features were also studied. Statistical analysis was performed with IBM® SPSS®.

Results

A cohort of 108 patients under antifibrotics (nintedanib n = 54; pirfenidone n = 54) was assessed. Lung function analysis showed an overall stabilization in FVC 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 < 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).

Conclusions

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.

Rationale

Longitudinal epidemiological and clinical data are needed to improve the management of patients with bronchiectasis developing nontuberculous mycobacterial (NTM) pulmonary disease.

Objectives

To describe the epidemiology, patient management, and treatment outcomes of NTM infections in patients with bronchiectasis enrolled in the United States Bronchiectasis and NTM Research Registry (US BRR).

Methods

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 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).

Results

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 Mycobacterium avium complex (MAC) and/or Mycobacterium abscessus 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 >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 (>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.

Conclusions

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.

Background and objectives

Chronic refractory cough is a challenging condition that requires a thorough evaluation and management approach. P2X3 receptors that are ATP-dependent play an important part in nerve fiber sensitization and pathological pain pathways. We conducted this systematic review and meta-analysis to determine the long-term safety and efficacy of P2X3 receptor antagonist drugs in chronic cough.

Methods

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.

Results

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 < 0.01), awake (daytime) cough frequency (MD = −7.18, 95% CI [−9.98 to 4.37], P < 0.01), and total Leicester Cough Questionnaire score (MD = 1.74, 95% CI [1.02 to 2.46], P < 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, dysgeusia, hypogeusia, and ageusia significantly increased between the P2X3 antagonist and placebo groups.

Conclusion

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.

Background

Airway epithelial cells epithelial mesenchymal transition (EMT) and lung fibroblasts extracellular matrix (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 cell proliferation and ECM deposition. However, the function of miR-143-3p in airway epithelial cells and lung fibroblasts remains unclear.

Methods

Cell viability was determined using MTT method, while cell migration was evaluated through scratch assay. EMT and ECM proteins were detected by western blot, RT-qPCR, and ELISA. To determine the level of miR-143-3p m⁶A methylation, we employed the meRIP-qPCR assay. Additionally, the binding of miR-143-3p with Smad3 were projected by bioinformatics and validated by dual luciferase reporter assays.

Results

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.

Conclusion

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.