Restore Lung Function Research Articles

Effectiveness of Threshold-Pressure Inspiratory Muscle Training on Pulmonary Rehabilitation in Children and Adolescents with Asthma.

The objective of this systematic review and meta-analysis was to assess the effectiveness of TIMT on pulmonary function in children and adolescents with asthma. We searched for randomized controlled clinical trials in the MEDLINE, Embase, the Cochrane Library, Web of Science, CINAHL, Sino Med, Wan fang, CNKI, and VIP until March 2024. In addition, the references included in the literature and the relevant systematic evaluation were manually traced in order to avoid the omission of any relevant literature. These trials compared TIMT against blank TIMT and conventional care. Eligible studies were assessed in terms of risk of bias and quality of evidence using RoB II tool. Where feasible, data were pooled and subjected to meta-analysis. The mean difference (MD) and 95% confidence interval (CI) were estimated by fixed effect models or random effect models. Six studies were included in the present meta-analysis involving 337 children and adolescents ranged from 4 to 18 years. The meta-analysis showed that TIMT could significantly improve lung function. Compared to the control group, TIMT can significantly improve FEV1 (MD 4.63 mL, 95% CI 2.64 to 6.62 mL, I2 = 4%), FVC (to the control group (MD 7.46 mL, 95% CI 5.09 to 9.82 mL, I2 = 0%), FEV1/FVC (MD 7.33%, 95% CI: 5.01 to 9.65%) and ACT (MD 1.86, 95% CI 0.96 to 2.75 mL, I2 = 12%) of patients at the end of intervention. There was no significant heterogeneity in these meta-analyses. In conclusion, the results of this systematic review and meta-analysis support the effectiveness of TIMT training in restoring lung function and relieving asthma symptoms of asthmatic children. More high-quality and RCTs with large sample size are urgently required to verify the conclusion.

The change of FeNO is correlated with asthma control and lung function

ObjectiveTo investigate the changes in fractional exhaled nitric oxide (FeNO) after treatment and the association between FeNO changes and the prognosis and lung function of children with asthma. MethodsA total of 144 children newly enrolled with non-standardized treatment of asthma were recruited between September 2020 and December 2021. The children were divided into two groups according to the initial FeNO (0 day), and the changes in FeNO after Budesonide/Formoterol Inhalation Powder Mist (B/FIPM) treatment were observed in different subgroups in correlation with future outcomes after 1 year (well controlled or partly controlled) and lung function. ResultsThe study showed that B/FIPM therapy significantly reduced FeNO levels and eosinophils (EOS) counts, improving pulmonary function (P < 0.01). FeNO levels significantly decreased in the well controlled group after 1 week treatment but not after 2 weeks. The partly controlled group showed sustained benefits after 2 weeks treatment (P < 0.01). Besides, among the patients with initial FeNO ≤35 ppb, the proportion of well controlled outcome was significantly higher in the group of ΔFeNO >0 (72.73 %) than that in the ΔFeNO ≤0 group (53.85 %) (P = 0.042). ConclusionB/FIPM is effective in reducing FeNO levels and EOS counts and restoring lung function in children with asthma. In addition, post-treatment changes in FeNO were predictive of prognosis and correlated with post-treatment lung function.

Restoring discarded porcine lungs by ex vivo removal of neutrophil extracellular traps

BackgroundBy causing inflammation and tissue damage, neutrophil extracellular traps (NETs) constitute an underlying mechanism of aspiration-induced lung injury, a major factor of the low utilization of donor lungs in lung transplantation (LTx). MethodTo determine whether NET removal during ex vivo lung perfusion (EVLP) can restore lung function and morphology in aspiration-damaged lungs, gastric aspiration lung injury was induced in 12 pigs. After confirmation of acute respiratory distress syndrome, the lungs were explanted and assigned to NET removal connected to EVLP (treated) (n=6) or EVLP only (non-treated) (n=6). Hemodynamic measurements were taken, and blood and tissue samples were collected to assess lung function, morphology, levels of cell-free DNA, extracellular histones, and nucleosomes as markers of NETs as well as cytokine levels. ResultsAfter EVLP and NET removal in porcine lungs, PaO2/FiO2 ratios increased significantly compared to those undergoing EVLP alone (p=0.0411). Treated lungs had lower cell-free DNA (p=0.0260) and lower levels of extracellular histones in EVLP perfusate than non-treated lungs (p=0.0260). According to histopathology, treated lungs showed less immune cell infiltration and less oedema compared with non-treated lungs which was reflected in decreased levels of pro-inflammatory cytokines in EVLP perfusate and BALF. ConclusionTo conclude, removing NETs during EVLP improved lung function and morphology in aspiration-damaged donor lungs. The ability to remove NETs during EVLP could represent a new therapeutic approach for LTx and potentially expand the donor pool for transplantation.

TROP2 promotes PINK1-mediated mitophagy and apoptosis to accelerate the progression of senile chronic obstructive pulmonary disease by up-regulating DRP1 expression

Chronic obstructive pulmonary disease (COPD) is a chronic airway inflammatory disease characterised by irreversible airflow limitation. The elderly are a vulnerable population for developing COPD. With the growth of age, physiological degenerative changes occur in the thorax, bronchus, lung and vascular wall, which can lead to age-related physiological attenuation of lung function in the elderly, so the prevalence of COPD increases with age. Its pathogenesis has not yet been truly clarified. Mitophagy plays an important role in maintaining the stability of mitochondrial function and intracellular environment by scavenging damaged mitochondria. Currently, studies have shown that trophoblast antigen 2 (TROP2) expression is up-regulated in airway basal cells of patients with COPD, suggesting that TROP2 is involved in the progression of COPD. However, whether it is involved in disease progression by regulating mitochondrial function remains unclear. In this study, compared with non-smoking non-COPD patients, the expression of TROP2 in lung tissues of smoking non-COPD patients and patients with COPD increased, and TROP2 expression in patients with COPD was higher than that in smoking non-COPD patients. To further explore the role of TROP2, we stimulated BEAS-2B with cigarette smoke to construct an in vitro model. We found that TROP2 expression increased, whereas TROP2 silencing reversed the cigarette smoke extract-induced decrease in mitochondrial membrane potential, increased reactive oxygen species content, decreased adenosine triphosphate (ATP) production, increased inflammatory factor secretion and increased apoptosis. In addition, we searched online bioinformatics and screened the gene dynamin-related protein 1 (DRP1) related to mitophagy as the research object. Co-IP assay verified the binding relationship between DRP1 and TROP2. Further study found that TROP2 promoted mitophagy and apoptosis of BEAS-2B cells by up-regulating the expression of DRP1. In addition, PTEN-induced putative kinase 1 (PINK1) is a potential binding protein of DRP1, and DRP1 accelerated mitophagy and apoptosis of BEAS-2B cells by promoting the expression of PINK1. We established a COPD SD rat model by cigarette smoke exposure and LPS instillation and treated it by intraperitoneal injection of si-TROP2. The results showed that TROP2 silencing restored lung function and reduced the secretion of inflammatory factors in bronchoalveolar lavage fluid. In conclusion, TROP2 can be used as a new reference for COPD treatment.

Inhibition the ubiquitination of ENaC and Na,K-ATPase with erythropoietin promotes alveolar fluid clearance in sepsis-induced acute respiratory distress syndrome

Sepsis-induced acute respiratory distress syndrome (ARDS) causes significant fatalities worldwide and lacks pharmacological intervention. Alveolar fluid clearance (AFC) plays a pivotal role in the remission of ARDS and is markedly impaired in the pathogenesis of ARDS. Here, we demonstrated that erythropoietin could effectively ameliorate lung injury manifestations and lethality, restore lung function and promote AFC in a rat model of lipopolysaccharide (LPS)-induced ARDS. Moreover, it was proven that EPO-induced restoration of AFC occurs through triggering the total protein expression of ENaC and Na,K-ATPase channels, enhancing their protein abundance in the membrane, and suppressing their ubiquitination for degeneration. Mechanistically, the data indicated the possible involvement of EPOR/JAK2/STAT3/SGK1/Nedd4–2 signaling in this process, and the pharmacological inhibition of the pathway markedly eliminated the stimulating effects of EPO on ENaC and Na,K-ATPase, and subsequently reversed the augmentation of AFC by EPO. Consistently, in vitro studies of alveolar epithelial cells paralleled with that EPO upregulated the expression of ENaC and Na,K-ATPase, and patch-clamp studies further demonstrated that EPO substantially strengthened sodium ion currents. Collectively, EPO could effectively promote AFC by improving ENaC and Na,K-ATPase protein expression and abundance in the membrane, dependent on inhibition of ENaC and Na,K-ATPase ubiquitination, and resulting in diminishing LPS-associated lung injuries.

Intermittent normobaric hypoxia therapy for COVID-19 survivors: a promising approach to recovery

This groundbreaking study delves into the transformative potential of Intermittent Normobaric Hypoxia Therapy (INHT) in a targeted cohort of 50 young adult COVID-19 survivors, aged 18 to 24 years. Through comprehensive pre- and post-INHT spirometry assessments, our research uncovers the nuanced respiratory benefits of this innovative therapy. The results showcase significant improvements in key spirometry parameters, emphasizing INHT's pivotal role in restoring lung function and fostering holistic respiratory well-being post-COVID-19

Network Pharmacology Followed by Experimental Validation to Explore the Mechanism of Stigmasterol in Sangbaipi Decoction Regulating PI3K/Akt Signaling to Alleviate Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

Sangbaipi decoction (SBPD), a traditional Chinese medicine (TCM) prescription, has been widely used to treat acute exacerbation of chronic obstructive pulmonary disease (AECOPD), while the underlying pharmacological mechanism remains unclear due to the complexity of composition. A TCM-active ingredient-drug target network of SBPD was constructed utilizing the TCM-Systems-Pharmacology database. AECOPD-relevant proteins were gathered from Gene Cards and the Online-Mendelian-Inheritance-in-Man database. Protein-protein interaction, GO and KEGG enrichment analyses of the targets from the intersection of SBPD and AECOPD targets were performed to identify the core signaling pathway, followed by molecular docking verification of its interaction with active ingredients. The network pharmacology results were checked using in-vivo experiments. To induce AECOPD, rats were exposure to combined tobacco smoke and lipopolysaccharide (LPS). Then rats underwent gavage with stigmasterol (SM) after successful modeling. The involvement of phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling was investigated using its inhibitor, LY294002. Lung function and histopathology were examined. The levels of inflammatory cytokines in the lung and serum were assessed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot and/or Enzyme-linked immunosorbent assay (ELISA). SM was recognized as an active ingredient of SBPD and stably bound to Akt1. SM improved lung function and histological abnormalities, concomitant with suppressed PI3K/Akt signaling, downregulated lung and serum Interleukin 6 (IL-6) and tumor necrosis factor-α (TNF-α) levels and serum transforming growth factor-β (TGF-β) levels and upregulated lung and serum Interleukin 10 (IL-10) levels in AECOPD rats. In AECOPD rats, LY294002 restored lung function, and it also improved lung histological abnormalities and inflammation, which was found to be potentiated by SM. SM targets PI3K/Akt signaling to reduce lung injury and inflammation in AECOPD rats.

Nanoparticles of Lactiplantibacillus plantarum K8 Reduce Staphylococcus aureus Respiratory Infection and Tumor Necrosis Factor Alpha- and Interferon Gamma-Induced Lung Inflammation.

Multiple studies have confirmed that Lactiplantibacillus plantarum has beneficial effects in respiratory diseases, including respiratory tract infections, asthma, and chronic obstructive pulmonary disease. However, the role of L. plantarum lysates in respiratory diseases is unclear. Staphylococcus aureus infects the lungs of mice, recruits immune cells, and induces structural changes in alveoli. Lung diseases can be further aggravated by inflammatory cytokines such as CCL2 and interleukin (IL)-6. In in vivo studies, L. plantarum K8 nanoparticles (K8NPs) restored lung function and prevented lung damage caused by S. aureus infection. They inhibited the S. aureus infection and the infiltration of immune cells and prevented the increase in goblet cell numbers in the lungs of S. aureus-infected mice. K8NPs suppressed the expression of CCL2 and IL-6, which were increased by the combination treatment of tumor necrosis factor alpha and interferon gamma (TI), in a dose-dependent manner. In in vitro studies, the anti-inflammatory effect of K8NPs in TI-treated A549 cells and TI-injected mice occurred through the reduction in activated mitogen-activated protein kinases and nuclear factor kappa-B. These findings suggest that the efficacy of K8NPs in controlling respiratory inflammation and infection can be used to develop functional materials that can prevent or alleviate respiratory diseases.

Longitudinal x-ray based lung function measurement for monitoring Nintedanib treatment response in a mouse model of lung fibrosis

Lung fibrosis (LF) is a chronic progressive, incurable, and debilitating condition of the lung, which is associated with different lung disease. Treatment options are still sparse. Nintedanib, an oral tyrosine kinase inhibitor, significantly slows the LF progression. However, there is a strong need of further research and the development of novel therapies. In this study, we used a correlative set-up that combines X-ray based lung function (XLF) with microCT and whole body plethysmography (WBP) for a comprehensive functional and structural evaluation of lung fibrosis (LF) as well as for monitoring response to orally administered Nintedanib in the mouse model of bleomycin induced LF. The decline in lung function as early as one week after intratracheal bleomycin instillation was reliably detected by XLF, revealing the lowest decay rate in the LF mice compared to healthy ones. Simultaneously performed microCT and WBP measurements corroborated XLF findings by exhibiting reduced lung volume V^{insp}_{mu CT} and tidal volume TV_{WBP}. In LF mice XLF also revealed profound improvement in lung function one week after Nintedanib treatment. This positive response to Nintedanib therapy was further substantiated by microCT and WBP measurements which also showed significantly improved V^{insp}_{mu CT} and TV_{WBP} in the Nintedanib treated mice. By comparing the XLF data to structural features assessing the extent of fibrosis obtained by ex-vivo high-resolution synchrotron radiation-based imaging and classical histology we demonstrate that: (1) a simple low dose x-ray measurement like XLF is sensitive enough to pick up treatment response, (2) Nintedanib treatment successfully improved lung function in a bleomycin induced LF mouse model and (3) differences between the fully restored lung function and the partially reduced fibrotic burden compared to healthy and untreated mice. The presented analysis pipeline underlines the importance of a combined functional and anatomical readout to reliably measure treatment response and could easily be adapted to other preclinical lung disease models.

Lung Microbiome as a Treatable Trait in Chronic Respiratory Disorders.

Once thought to be a sterile environment, it is now established that lungs are populated by various microorganisms that participate in maintaining lung function and play an important role in shaping lung immune surveillance. Although our comprehension of the molecular and metabolic interactions between microbes and lung cells is still in its infancy, any event causing a persistent qualitative or quantitative variation in the composition of lung microbiome, termed "dysbiosis", has been virtually associated with many respiratory diseases. A deep understanding of the composition and function of the "healthy" lung microbiota and how dysbiosis can cause or participate in disease progression will be pivotal in finding specific therapies aimed at preventing diseases and restoring lung function. Here, we review lung microbiome dysbiosis in different lung pathologies and the mechanisms by which these bacteria can cause or contribute to the severity of the disease. Furthermore, we describe how different respiratory disorders can be caused by the same pathogen, and that the real pathogenetic mechanism is not only dependent by the presence and amount of the main pathogen but can be shaped by the interaction it can build with other bacteria, fungi, and viruses present in the lung. Understanding the nature of this bacteria crosstalk could further our understanding of each respiratory disease leading to the development of new therapeutic strategies.

The Role of IL-33/ST2 in COPD and Its Future as an Antibody Therapy.

COPD is a leading cause of mortality and morbidity worldwide and is associated with a high socioeconomic burden. Current treatment includes the use of inhaled corticosteroids and bronchodilators, which can help to improve symptoms and reduce exacerbations; however, there is no solution for restoring lung function and the emphysema caused by loss of the alveolar tissue. Moreover, exacerbations accelerate progression and challenge even more the management of COPD. Mechanisms of inflammation in COPD have been investigated over the past years, thus opening new avenues to develop novel targeted-directed therapies. Special attention has been paid to IL-33 and its receptor ST2, as they have been found to mediate immune responses and alveolar damage, and their expression is upregulated in COPD patients, which correlates with disease progression. Here we summarize the current knowledge on the IL-33/ST2 pathway and its involvement in COPD, with a special focus on developed antibodies and the ongoing clinical trials using anti-IL-33 and anti-ST2 strategies in COPD patients.

MSC-EXO and tempol ameliorate bronchopulmonary dysplasia in newborn rats by activating HIF-1α.

Bronchopulmonary dysplasia (BPD) is a major complication of premature infants and an important cause of morbidity and mortality. This study investigates the effect of the combination of mesenchymal stem cells-derived exosomes (MSC-EXO) and tempol on BPD and analyzes its mechanism. MSC-EXO was extracted by centrifugation and identified by transmission electron microscopy (TEM), nanoparticle tracking analysis, and western blot analysis(WB). Tidal volume (TV), minute ventilation (MV), peak inspiratory flow (PIF), and dynamic pulmonary compliance (Cdyn) of rats were measured by BuxCo pulmonary function experimental platform. Hematoxylin-eosin staining was performed to observe the lung morphology and radical alveolar count (RAC)and mean linear intercept (MLI) were assessed. Immunofluorescence (IF) was conducted to detect the expression of CD31 and α-SMA in pulmonary blood vessels. The kits were used to calculate malondialdehyde (MDA), superoxide dismutase (SOD), and total antioxidant capacity (TAOC) concentration in lung tissue. Enzyme linked immunosorbent assaywas applied to detect the levels of IL-1β, IL-17, IL-6, and IFN-γ in bronchoalveolar lavage fluid. In addition, the expressions of HIF-1α, vascular endothelial growth factor(VEGF), p-PI3K, and p-AKT were analyzed by WB and IF. We successfully extracted and identified MSC-EXO. In BPD rats, TV, MV, PIF, and Cdyn decreased, alveoli were simplified, and the number of interalveoli small vessels, blood vessel density decreased. Moreover, RAC, CD31, TAOC, and SOD decreased, and MLI, α-SMA, MDA, IL-1β, IL-17, IL-6, and IFN-γ increased, which was reversed by the combination of MSC-EXO and tempol treatment after combined treatment. In addition, the expression levels of HIF-1α, VEGF, p-PI3K, and p-AKT were increased after combined treatment. Combined treatment could improve lung tissue injury, promote pulmonary vascular remodeling, restore lung function, and inhibit oxidative stress in BPD rats. These effects were achieved through activation of HIF-1α.

The Use of Tai Chi and Qigong to Mediate Long-Haul COVID-19 Symptoms: Case Report

Introduction: Although new COVID-19 cases have been decreasing globally, long-haul COVID-19 continues to present a challenge. Long-haul COVID-19 symptoms, such as dyspnea, fatigue, cognitive impairments, gastrointestinal distress, and mood changes, can remain for months after initial infection in 10-30% of individuals infected with COVID-19. These symptoms can limit daily function and decrease quality of life. Given the recency of the disease, very little literature exists on the causes of long-haul COVID-19 and few treatment options are available for afflicted individuals. This case report describes the use of the Eastern medicine practices of Tai Chi and Qigong as a possible technique to increase lung function and thus daily function in those with long-haul COVID. Both Tai Chi and Qigong were developed thousands of years ago in China and utilized as part of traditional Chinese medicine. They are forms of gentle, low-intensity exercise involving slow, continuous movements and stretches that focus on alignment, coordination, and breathing control. Previous studies have shown that Tai Chi and Qigong provide beneficial effects in those experiencing mood disorders, chronic pain, cardiovascular issues, fibromyalgia, and chronic obstructive pulmonary disease. Although practitioners have proposed the use of Tai Chi and Qigong in patients with COVID-19, no data exists on the outcomes. Materials and Methods: This case report presents a patient with pre-existing conditions of obesity, gastroesophageal reflux disease, cervical cancer, cataract surgery, and sinus surgery initially diagnosed with COVID-19 with symptoms of acute dyspnea, dizziness, cough, headache, chills, fever, rhinorrhea, and sore throat. She was later diagnosed with long-haul COVID-19 with symptoms of dyspnea, fatigue, and dizziness on exertion and gastrointestinal distress. The patient practiced Tai Chi and Qigong three to four times weekly for about 30 min on average. Results: The patient experienced decreases in resting heart rate and weight and an increase in oxygen saturation level (SpO2) from 83% to 96%, indicating that Tai Chi and Qigong may have the potential to restore lung function. Conclusion: Thus, we propose that Tai Chi and Qigong can be an easily accessible, low-intensity, and cost-effective technique to increase lung function and quality of life in patients with long-haul COVID-19.

Efficacy of surfactant therapy of ARDS induced by hydrochloric acid aspiration followed by ventilator-induced lung injury - an animal study.

The development of acute respiratory distress syndrome (ARDS) is known to be independently attributable to aspiration-induced lung injury. Mechanical ventilation as a high pressure/volume support to maintain sufficient oxygenation of a patient could initiate ventilator-induced lung injury (VILI) and thus contribute to lung damage. Although these phenomena are rare in the clinic, they could serve as the severe experimental model of alveolar-capillary membrane deterioration. Lung collapse, diffuse inflammation, alveolar epithelial and endothelial damage, leakage of fluid into the alveoli, and subsequent inactivation of pulmonary surfactant, leading to respiratory failure. Therefore, exogenous surfactant could be considered as a therapy to restore lung function in experimental ARDS. This study aimed to investigate the effect of modified porcine surfactant in animal model of severe ARDS (P/F ratio </=13.3 kPa) induced by intratracheal instillation of hydrochloric acid (HCl, 3 ml/kg, pH 1.25) followed by VILI (V(T) 20 ml/kg). Adult rabbits were divided into three groups: untreated ARDS, model treated with a bolus of poractant alfa (Curosurf®, 2.5 ml/kg, 80 mg phospholipids/ml), and healthy ventilated animals (saline), which were oxygen-ventilated for an additional 4 h. The lung function parameters, histological appearance, degree of lung edema and levels of inflammatory and oxidative markers in plasma were evaluated. Whereas surfactant therapy with poractant alfa improved lung function, attenuated inflammation and lung edema, and partially regenerated significant changes in lung architecture compared to untreated controls. This study indicates a potential of exogenous surfactant preparation in the treatment of experimental ARDS.

The effectiveness of the inclusion of hyperbaric oxygenation in the complex therapy of patients with COVID-19: retrospective study

The effectiveness of the inclusion of hyperbaric oxygenation in the complex therapy of patients with COVID-19: retrospective study

217.7: Neutrophil Extracellular Traps Removal Using Ex Vivo Lung Perfusion Restored Lung Function in Gastric Aspiration Damaged Porcine Lungs

Background: Lung transplantation (LTx) is an established therapeutic option for end-stage pulmonary disease. However, it remains hampered by donor lung scarcity. Treatments which could regenerate lungs rejected for transplant should be explored in order to combat waiting list mortality. Aspiration induced acute lung injury (ALI) is one of the contributes to the low utilization of donor lungs. Neutrophil extracellular traps (NETs) are implicated in the inflammation profile of ALI. Reduction of NETs could be used as a therapeutic option with the arrival of devices specific to their removal. NucleoCapture device selectively removes NETs from the blood by utilizing human histone H1.3 protein conjugated to polymer beads. This study investigated the impact of the NETs capture device during ex vivo lung perfusion (EVLP) on ALI damaged lungs. Methods: Healthy pigs (n=12) were stratified into two groups, treated (n=6) and not treated (n=6). All animals received 4ml/kg body weight gastric content distributed equally between the different lung segments using a bronchoscopy to induce acute lung injury. Mild to moderate ARDS was developed over 6 hours and confirmed via blood gas values, chest x-ray imaging and histological examination. Lungs were subsequently explanted en bloc and placed on EVLP for 4 hours. Treated lungs were placed in line with a NucleoCapture device connected to the EVLP circuit and the non-treated group underwent the same EVLP protocol without the device. Results: Aspiration induced ALI was induced in all subjects as confirmed by infiltration on chest x-ray, histopathological examination and by PaO2/FiO2 ratio. Following treatment with the NucleoCapture device during 4 hours of EVLP, the PaO2/FiO2 ratio was significantly increased compared to non-treated lungs and was found to surpass the threshold values suitable for transplantation. Furthermore, macroscopic evaluation of the treated lungs demonstrated improvement relative to both the initial injury as well as comparison with the non-treated cohort. Conclusions: Removal of NETs using the NucleoCapture device did restored lung function in aspiration damaged lungs. The amelioration of lung function by removing NETs shows potential clinical use of the device to increase the donor lung pool for lung transplantation.

A Novel Triple Combination To Combat Serious Infections with Carbapenem-Resistant Acinetobacter baumannii in a Mouse Pneumonia Model.

ABSTRACTThe ongoing crisis of antimicrobial resistance demands novel combinations between antimicrobials and nonantimicrobials to manage infections caused by highly resistant pathogens. This study aimed to evaluate the effect of combining sodium ascorbate and/or apo-transferrin with imipenem, forming double and triple combinations, against 20 multiple-carbapenemase-producing Acinetobacter baumannii strains using the checkerboard test, time-kill assay, and disc diffusion test. The results of the checkerboard assay revealed that all double combinations showed indifference, while only triple combination recorded a synergistic effect (fractional inhibitory concentration index [FICI] < 0.8) in 95% the test isolates. Moreover, the MIC of imipenem (MICimp) was strongly reduced (up to 128-fold reduction) after treatment with the triple combination against highly resistant isolates and reached the susceptible range. The time-kill assay revealed that the triple combination led to a 4-log10 reduction in the CFU at 8 h compared with the initial bacterial count, and no viable count was recorded at 10 h. The mouse pneumonia model showed restoration of lung function and structure, with mild to moderate residual inflammation and moderately congested vessels observed 8 h following administration of the triple rescue therapy. Additionally, normal lungs with normal patent alveoli were detected 72 h following treatment. Accordingly, sodium ascorbate and apo-transferrin are promising adjunct biological agents with the potential to restore the effectiveness of critically essential antibiotics like imipenem, commonly used for the treatment of A. baumannii infections.IMPORTANCE Combination therapy provides a perspective to threat multidrug-resistant (MDR) strains. The present study sheds light on a novel and effective triple combination against carbapenem-resistant A. baumannii. Our in vitro results showed that combining imipenem with apo-transferrin and sodium ascorbate yielded synergism in 95% of test isolates, and this was associated with a marked reduction in imipenem MIC, shifting it below the breakpoint. Furthermore, a bactericidal effect was recorded, with no viable count detected at 10 h. An in vivo murine model of pneumonia was induced to mimic human disease. The triple combination therapy restored lung function and structure, with mild to moderate residual inflammation and moderately congested vessels observed 8 h following the initiation of therapy. Therefore, our findings suggest novel insights about a promising new combination therapy against highly resistant carbapenemase-producing A. baumannii to restore the effectiveness of imipenem.

Reduction of primary graft dysfunction using cytokine adsorption during organ preservation and after lung transplantation

Despite improvements, lung transplantation remains hampered by both a scarcity of donor organs and by mortality following primary graft dysfunction (PGD). Since acute respiratory distress syndrome (ARDS) limits donor lungs utilization, we investigated cytokine adsorption as a means of treating ARDS donor lungs. We induced mild to moderate ARDS using lipopolysaccharide in 16 donor pigs. Lungs were then treated with or without cytokine adsorption during ex vivo lung perfusion (EVLP) and/or post-transplantation using extracorporeal hemoperfusion. The treatment significantly decreased cytokine levels during EVLP and decreased levels of immune cells post-transplantation. Histology demonstrated fewer signs of lung injury across both treatment periods and the incidence of PGD was significantly reduced among treated animals. Overall, cytokine adsorption was able to restore lung function and reduce PGD in lung transplantation. We suggest this treatment will increase the availability of donor lungs and increase the tolerability of donor lungs in the recipient.

Live attenuated pertussis vaccine for prevention and treatment of allergic airway inflammation in mice

Live attenuated vaccines often have beneficial non-specific effects, protecting against heterologous infectious and non-infectious diseases. We have developed a live attenuated pertussis vaccine, named BPZE1, currently in advanced clinical development. Here, we examined the prophylactic and therapeutic potential of its pertactin-deficient derivative BPZE1P in a mouse model of house dust mite (HDM)-induced allergic airway inflammation (AAI). BPZE1P was given nasally either before or after sensitization with HDM, followed by HDM challenge, or between two challenge episodes. Vaccination prior to sensitization reduced resistance in the airways, the numbers of infiltrating eosinophils and the concentrations of proinflammatory cytokines, such as IL-1α, IL-1β and IL-33, in the lungs but had no effect on Th2 cytokine levels. BPZE1P also protected when delivered after sensitization or between two challenge episodes. However, in this case the levels of Th2 cytokines in the lung were decreased without significant effects on IL-1α, IL-1β and IL-33 production. The vaccine restored lung function and decreased eosinophil influx in the lungs of HDM-treated mice. BPZE1P has a better take than BPZE1 in hosts vaccinated with acellular pertussis vaccines. Therefore, it has interesting potential as a preventive and therapeutic agent against AAI, even in acellular pertussis-vaccinated populations.

Stem Cell-Based Regenerative Therapy and Derived Products in COPD: A Systematic Review and Meta-Analysis.

COPD is an incurable disorder, characterized by a progressive alveolar tissue destruction and defective mechanisms of repair and defense leading to emphysema. Currently, treatment for COPD is exclusively symptomatic; therefore, stem cell-based therapies represent a promising therapeutic approach to regenerate damaged structures of the respiratory system and restore lung function. The aim of this study was to provide a quantitative synthesis of the efficacy profile of stem cell-based regenerative therapies and derived products in COPD patients. A systematic review and meta-analysis was performed according to PRISMA-P. Data from 371 COPD patients were extracted from 11 studies. Active treatments elicited a strong tendency towards significance in FEV1 improvement (+71 mL 95% CI -2–145; p = 0.056) and significantly increased 6MWT (52 m 95% CI 18–87; p < 0.05) vs. baseline or control. Active treatments did not reduce the risk of hospitalization due to acute exacerbations (RR 0.77 95% CI 0.40–1.49; p > 0.05). This study suggests that stem cell-based regenerative therapies and derived products may be effective to treat COPD patients, but the current evidence comes from small clinical trials. Large and well-designed randomized controlled trials are needed to really quantify the beneficial impact of stem cell-based regenerative therapy and derived products in COPD.