SUL-151 Decreases Airway Neutrophilia as a Prophylactic and Therapeutic Treatment in Mice after Cigarette Smoke Exposure

Chronic obstructive pulmonary disease (COPD) caused by cigarette smoke (CS) is featured by oxidative stress and chronic inflammation. Due to the poor efficacy of standard glucocorticoid therapy, new treatments are required. Here, we investigated whether the novel compound SUL-151 with mitoprotective properties can be used as a prophylactic and therapeutic treatment in a murine CS-induced inflammation model. SUL-151 (4 mg/kg), budesonide (500 μg/kg), or vehicle were administered via oropharyngeal instillation in this prophylactic and therapeutic treatment setting. The number of immune cells was determined in the bronchoalveolar lavage fluid (BALF). Oxidative stress response, mitochondrial adenosine triphosphate (ATP) production, and mitophagy-related proteins were measured in lung homogenates. SUL-151 significantly decreased more than 70% and 50% of CS-induced neutrophils in BALF after prophylactic and therapeutic administration, while budesonide showed no significant reduction in neutrophils. Moreover, SUL-151 prevented the CS-induced decrease in ATP and mitochondrial mtDNA and an increase in putative protein kinase 1 expression in the lung homogenates. The concentration of SUL-151 was significantly correlated with malondialdehyde level and radical scavenging activity in the lungs. SUL-151 inhibited the increased pulmonary inflammation and mitochondrial dysfunction in this CS-induced inflammation model, which implied that SUL-151 might be a promising candidate for COPD treatment

The Combination Therapy of Dietary Galacto-Oligosaccharides With Budesonide Reduces Pulmonary Th2 Driving Mediators and Mast Cell Degranulation in a Murine Model of House Dust Mite Induced Asthma

Background: Dietary non-digestible galacto-oligosaccharides (GOS) suppress allergic responses in mice sensitized and challenged with house dust mite (HDM). Budesonide is the standard therapy for allergic asthma in humans but is not always completely effective.Aim: To compare the efficacy of budesonide or different doses of GOS alone or with a combination therapy of budesonide and GOS on HDM-allergic responses in mice.Methods:BALB/c mice were sensitized and challenged with HDM, while fed a control diet or a diet supplemented with 1 or 2.5 w/w% GOS, and either or not oropharyngeally instilled with budesonide. Systemic and local inflammatory markers, such as mucosal mast cell protease-1 (mMCP-1) in serum, pulmonary CCL17, CCL22, and IL-33 concentrations and inflammatory cell influx in the bronchoalveolar lavage fluid (BALF) were determined.Results: Budesonide or GOS alone suppressed the number of eosinophils in the BALF of HDM allergic mice whereas budesonide either or not combined with GOS lowered both eosinophil and lymphocyte numbers in the BALF of HDM-allergic mice. Both 1 w/w% and 2.5 w/w% GOS and/or budesonide suppressed serum mMCP-1 concentrations. However, budesonide nor GOS alone was capable of reducing Th2 driving chemokines CCL17, CCL22 and IL-33 protein levels in supernatants of lung homogenates of HDM allergic mice, whereas the combination therapy did. Moreover, IL-13 concentrations were only significantly suppressed in mice treated with budesonide while fed GOS. A similar tendency was observed for the frequency of GATA3+CD4+ Th2 and CD4+RORγt+ Th17 cells in the lungs of the allergic mice.Conclusion: Dietary intervention using GOS may be a novel way to further improve the efficacy of anti-inflammatory drug therapy in allergic asthma by lowering Th2 driving mediators and mast cell degranulation

Exploring the Modulatory Effect of High-Fat Nutrition on Lipopolysaccharide-Induced Acute Lung Injury in Vagotomized Rats and the Role of the Vagus Nerve

During esophagectomy, the vagus nerve is transected, which may add to the development of postoperative complications. The vagus nerve has been shown to attenuate inflammation and can be activated by a high-fat nutrition via the release of acetylcholine. This binds to α7 nicotinic acetylcholine receptors (α7nAChR) and inhibits α7nAChR-expressing inflammatory cells. This study investigates the role of the vagus nerve and the effect of high-fat nutrition on lipopolysaccharide (LPS)-induced lung injury in rats. Firstly, 48 rats were randomized in 4 groups as follows: sham (sparing vagus nerve), abdominal (selective) vagotomy, cervical vagotomy and cervical vagotomy with an α7nAChR-agonist. Secondly, 24 rats were randomized in 3 groups as follows: sham, sham with an α7nAChR-antagonist and cervical vagotomy with an α7nAChR-antagonist. Finally, 24 rats were randomized in 3 groups as follows: fasting, high-fat nutrition before sham and high-fat nutrition before selective vagotomy. Abdominal (selective) vagotomy did not impact histopathological lung injury (LIS) compared with the control (sham) group (p > 0.999). There was a trend in aggravation of LIS after cervical vagotomy (p = 0.051), even after an α7nAChR-agonist (p = 0.090). Cervical vagotomy with an α7nAChR-antagonist aggravated lung injury (p = 0.004). Furthermore, cervical vagotomy increased macrophages in bronchoalveolar lavage (BAL) fluid and negatively impacted pulmonary function. Other inflammatory cells, TNF-α and IL-6, in the BALF and serum were unaffected. High-fat nutrition reduced LIS after sham (p = 0.012) and selective vagotomy (p = 0.002) compared to fasting. vagotomy. This study underlines the role of the vagus nerve in lung injury and shows that vagus nerve stimulation using high-fat nutrition is effective in reducing lung injury, even after selective vagotomy

Changes in intestinal homeostasis and immunity in a cigarette smoke- and LPS-induced murine model for COPD: the lung-gut axis

Chronic obstructive pulmonary disease (COPD) is often associated with intestinal comorbidities. In this study, changes in intestinal homeostasis and immunity in a cigarette smoke (CS)- and lipopolysaccharide (LPS)-induced COPD model were investigated. Mice were exposed to cigarette smoke or air for 72 days, except days 42, 52, and 62 on which the mice were treated with saline or LPS via intratracheal instillation. Cigarette smoke exposure increased the airway inflammatory cell numbers, mucus production, and different inflammatory mediators, including C-reactive protein (CRP) and keratinocyte-derived chemokine (KC), in bronchoalveolar lavage (BAL) fluid and serum. LPS did not further impact airway inflammatory cell numbers or mucus production but decreased inflammatory mediator levels in BAL fluid. T helper (Th) 1 cells were enhanced in the spleen after cigarette smoke exposure; however, in combination with LPS, cigarette exposure caused an increase in Th1 and Th2 cells. Histomorphological changes were observed in the proximal small intestine after cigarette smoke exposure, and addition of LPS had no effect. Cigarette smoke activated the intestinal immune network for IgA production in the distal small intestine that was associated with increased fecal sIgA levels and enlargement of Peyer's patches. Cigarette smoke plus LPS decreased fecal sIgA levels and the size of Peyer's patches. In conclusion, cigarette smoke with or without LPS affects intestinal health as observed by changes in intestinal histomorphology and immune network for IgA production. Elevated systemic mediators might play a role in the lung-gut cross talk. These findings contribute to a better understanding of intestinal disorders related to COPD

LAIR-1 Limits Neutrophilic Airway Inflammation

Neutrophils are crucial to antimicrobial defense, but excessive neutrophilic inflammation induces immune pathology. The mechanisms by which neutrophils are regulated to prevent injury and preserve tissue homeostasis are not completely understood. We recently identified the collagen receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1 as a functional inhibitory receptor on airway-infiltrated neutrophils in viral bronchiolitis patients. In the current study, we sought to examine the role of LAIR-1 in regulating airway neutrophil responses in vivo. LAIR-1-deficient (Lair1−/−) and wild-type mice were infected with respiratory syncytial virus (RSV) or exposed to cigarette smoke as commonly accepted models of neutrophil-driven lung inflammation. Mice were monitored for cellular airway influx, weight loss, cytokine production, and viral loads. After RSV infection, Lair1−/− mice show enhanced airway inflammation accompanied by increased neutrophil and lymphocyte recruitment to the airways, without effects on viral loads or cytokine production. LAIR-1-Fc administration in wild type mice, which blocks ligand induced LAIR-1 activation, augmented airway inflammation recapitulating the observations in Lair1−/− mice. Likewise, in the smoke-exposure model, LAIR-1 deficiency enhanced neutrophil recruitment to the airways and worsened disease severity. Intranasal CXCL1–mediated neutrophil recruitment to the airways was enhanced in mice lacking LAIR-1, supporting an intrinsic function of LAIR-1 on neutrophils. In conclusion, the immune inhibitory receptor LAIR-1 suppresses neutrophil tissue migration and acts as a negative regulator of neutrophil-driven airway inflammation during lung diseases. Following our recent observations in humans, this study provides crucial in-vivo evidence that LAIR-1 is a promising target for pharmacological intervention in such pathologies

Оптимизация магнитной пружины конструкции ''два постоянных магнита''

Изучена возможность оптимизации магнитной пружины типа ''два постоянных магнита''. Проведено теоретическое исследование зависимости усилия втягивания (вытягивания) и длины рабочего хода пружины от ее геометрических размеров. Все полученные результаты были подтверждены экспериментально. Отмечается хорошее соответствие теоретических и экспериментальных результатов. Установлены оптимальные соотношения между диаметрами внешнего и внутреннего цилиндрических магнитов для получения максимального усилия втягивания при заданной длине хода пружины. Предложена перспективная конструкция магнитной пружины с применением торцевого диска и проведены ее экспериментальные исследования.Вивчено можливість оптимізації магнітної пружини типу ''два постійні магніти''. Проведено теоретичне дослідження взаємозв'язку геометричних розмірів пружини з її зусиллям втягування (витягування) і довжиною робочого ходу. Всі отримані результати було підтверджено експериментально. Відзначається хороша відповідність теоретичних і експериментальних результатів. Встановлено оптимальні співвідношення між діаметрами зовнішнього й внутрішнього циліндричних магнітів для отримання максимального зусилля втягування при заданій довжині ходу пружини. Запропоновано перспективну конструкцію магнітної пружини із застосуванням торцевого диску й проведено її експериментальні дослідження.Optimization possibilities of a magnetic spring (''two permanent magnets'' type) are investigated. The theoretical calculation of the relationship of geometrical sizes and forces is carried out. All theoretical results are checked experimentally. A very good agreement of theoretical and experimental data is detected. The optimal ratio between two diameters of cylinder magnets for the maximal force at a given spring length is calculated. The perspective construction of a magnetic spring with applying the butt-end soft magnetic material disk is offered, and its experimental tests are carried out

Effects of a nutritional intervention on impaired behavior and cognitive function in an emphysematous murine model of COPD with endotoxin-induced lung inflammation

One cluster of the extrapulmonary manifestations in chronic obstructive pulmonary disease (COPD) is related to the brain, which includes anxiety, depression and cognitive impairment. Brain-related comorbidities are related to worsening of symptoms and increased mortality in COPD patients. In this study, a murine model of COPD was used to examine the effects of emphysema and repetitive pulmonary inflammatory events on systemic inflammatory outcomes and brain function. In addition, the effect of a dietary intervention on brain-related parameters was assessed. Adult male C57Bl/6J mice were exposed to elastase or vehicle intratracheally (i.t.) once a week on three consecutive weeks. Two weeks after the final administration, mice were i.t. exposed to lipopolysaccharide (LPS) or vehicle for three times with a 10 day interval. A dietary intervention enriched with omega-3 PUFAs, prebiotic fibers, tryptophan and vitamin D was administered from the first LPS exposure onward. Behavior and cognitive function, the degree of emphysema and both pulmonary and systemic inflammation as well as blood-brain barrier (BBB) integrity and neuroinflammation in the brain were assessed. A lower score in the cognitive test was observed in elastase-exposed mice. Mice exposed to elastase plus LPS showed less locomotion in the behavior test. The enriched diet seemed to reduce anxiety-like behavior over time and cognitive impairments associated with the presented COPD model, without affecting locomotion. In addition, the enriched diet restored the disbalance in splenic T-helper 1 (Th1) and Th2 cells. There was a trend toward recovering elastase plus LPS-induced decreased expression of occludin in brain microvessels, a measure of BBB integrity, as well as improving expression levels of kynurenine pathway markers in the brain by the enriched diet. The findings of this study demonstrate brain-associated comorbidities - including cognitive and behavioral impairments - in this murine model for COPD. Although no changes in lung parameters were observed, exposure to the specific enriched diet in this model appeared to improve systemic immune disbalance, BBB integrity and derailed kynurenine pathway which may lead to reduction of anxiety-like behavior and improved cognition

Non-digestible oligosaccharides partially prevent the development of LPS-induced lung emphysema in mice

Chronic obstructive pulmonary disease (COPD), a progressive inflammatory disorder, is also known as a systemic inflammatory disease, in which the gut-lung interaction plays an important role. The use of non-digestible oligosaccharides (NDOs) has gained attention in airway diseases due to their systemic effects on inflammatory markers. Here, the preventive effects of specific non-digestible oligosaccharides (GOS/lcFOS/lvPectin) were investigated in a murine lipopolysaccharide (LPS)-induced emphysema model. Nasal LPS-installations were used to induce emphysema in male BALB/c mice. Two weeks prior to the first LPS challenge, mice received GOS/lcFOS/lvPectin (9:1:2) mixture by gavage (25 mg NDOs/200 μl PBS) five days a week until day 28. The LPS-induced neutrophil influx in bronchoalveolar lavage fluid (BALF) decreased by >60% after intervention with GOS/lcFOS/lvPectin and the development of lung emphysema, measured by mean linear intercept, was prevented. Macroscopic examination of heart tissue revealed that GOS/lcFOS/lvPectin pretreatment attenuated the LPS-induced increase in right ventricular heart hypertrophy. In summary, GOS/lcFOS/lvPectin prevented characteristic features of COPD in the LPS-induced lung emphysema model. Since no therapy is available to stop or prevent development of COPD, oligosaccharides may have potential to be used as stand alone or in combination with other anti-inflammatory nutrients or drugs to diminish disease progression in COPD

Crude Turmeric Extract Improves the Suppressive Effects of Lactobacillus rhamnosus GG on Allergic Inflammation in a Murine Model of House Dust Mite-Induced Asthma

There is a strong correlation between dysregulation of the gastrointestinal microbiota and development of allergic diseases. The most prevalent therapies for relieving asthma symptoms are associated with serious side effects, and therefore novel approaches are needed. Our objective was to elucidate whether oral administration of Lactobacillus rhamnosus GG (LGG) as a probiotic or turmeric powder (TP) as a prebiotic or both as a synbiotic mitigate allergic inflammation including lung function, airway inflammatory cell infiltration, Th2 cytokines/chemokine in a murine model of house dust mite (HDM)-induced asthma. BALB/c mice were intranasally sensitized and challenged with HDM received TP (20 mg/Kg mouse), or/and LGG (105 or 107 cfu/ml), or both orally. Interestingly, the synbiotic intervention (HDM-TP-LGG E7) specifically suppress the developement of airway hyperresponsiveness in response to methacholine. Besides, our synbiotic, TP, and LGG strongly down-regulated eosinophilia, IL-5, CCL17, IL-13. In terms of T cell response, CD4+ Th2 cells and CD4+ Th17 population were reduced in the splenocytes of the treatment groups compared to control. The synbiotic group not only elevated CD25+Foxp3+Treg frequency compared to asthmatic group, but also increased T reg cells compared to the probiotic group. The synbiotic also indicated the superior effect in suppressing Th2 cells compared to probiotic. Although, TP and LGG alone displayed suppressive effects, this study showed that the combination therapy consisting of TP and LGG (synbiotic) is more effective in some of the parameters than either of the treatments alone. This novel synbiotic, might be considered as a potential food-based drug for translational medicine and can possibly be used along with corticosteroid treatment

Non-digestible oligosaccharides partially prevent the development of LPS-induced lung emphysema in mice

Chronic obstructive pulmonary disease (COPD), a progressive inflammatory disorder, is also known as a systemic inflammatory disease, in which the gut-lung interaction plays an important role. The use of non-digestible oligosaccharides (NDOs) has gained attention in airway diseases due to their systemic effects on inflammatory markers. Here, the preventive effects of specific non-digestible oligosaccharides (GOS/lcFOS/lvPectin) were investigated in a murine lipopolysaccharide (LPS)-induced emphysema model. Nasal LPS-installations were used to induce emphysema in male BALB/c mice. Two weeks prior to the first LPS challenge, mice received GOS/lcFOS/lvPectin (9:1:2) mixture by gavage (25 mg NDOs/200 μl PBS) five days a week until day 28. The LPS-induced neutrophil influx in bronchoalveolar lavage fluid (BALF) decreased by >60% after intervention with GOS/lcFOS/lvPectin and the development of lung emphysema, measured by mean linear intercept, was prevented. Macroscopic examination of heart tissue revealed that GOS/lcFOS/lvPectin pretreatment attenuated the LPS-induced increase in right ventricular heart hypertrophy. In summary, GOS/lcFOS/lvPectin prevented characteristic features of COPD in the LPS-induced lung emphysema model. Since no therapy is available to stop or prevent development of COPD, oligosaccharides may have potential to be used as stand alone or in combination with other anti-inflammatory nutrients or drugs to diminish disease progression in COPD