Ghrelin therapy improves lung and cardiovascular function in experimental emphysema.

BACKGROUND: Emphysema is a progressive disease characterized by irreversible airspace enlargement followed by a decline in lung function. It also causes extrapulmonary effects, such as loss of body mass and cor pulmonale, which are associated with shorter survival and worse clinical outcomes. Ghrelin, a growth-hormone secretagogue, stimulates muscle anabolism, has anti-inflammatory effects, promotes vasodilation, and improves cardiac performance. Therefore, we hypothesized that ghrelin might reduce lung inflammation and remodelling as well as improve lung mechanics and cardiac function in experimental emphysema. METHODS: Forty female C57BL/6 mice were randomly assigned into two main groups: control (C) and emphysema (ELA). In the ELA group (n=20), animals received four intratracheal instillations of pancreatic porcine elastase (PPE) at 1-week intervals. C animals (n=20) received saline alone (50 µL) using the same protocol. Two weeks after the last instillation of saline or PPE, C and ELA animals received ghrelin or saline (n=10/group) intraperitoneally (i.p.) daily, during 3 weeks. Dual-energy X-ray absorptiometry (DEXA), echocardiography, lung mechanics, histology, and molecular biology were analysed. RESULTS: In elastase-induced emphysema, ghrelin treatment decreased alveolar hyperinflation and mean linear intercept, neutrophil infiltration, and collagen fibre content in the alveolar septa and pulmonary vessel wall; increased elastic fibre content; reduced M1-macrophage populations and increased M2 polarization; decreased levels of keratinocyte-derived chemokine (KC, a mouse analogue of interleukin-8), tumour necrosis factor-α, and transforming growth factor-ß, but increased interleukin-10 in lung tissue; augmented static lung elastance; reduced arterial pulmonary hypertension and right ventricular hypertrophy on echocardiography; and increased lean mass. CONCLUSION: In the elastase-induced emphysema model used herein, ghrelin not only reduced lung damage but also improved cardiac function and increased lean mass. These findings should prompt further studies to evaluate ghrelin as a potential therapy for emphysema.

Controlled invasive mechanical ventilation strategies in obese patients undergoing surgery.

INTRODUCTION: The obesity prevalence is increasing in surgical population. As the number of obese surgical patients increases, so does the demand for mechanical ventilation. Nevertheless, ventilatory strategies in this population are challenging, since obesity results in pathophysiological changes in respiratory function. Areas covered: We reviewed the impact of obesity on respiratory system and the effects of controlled invasive mechanical ventilation strategies in obese patients undergoing surgery. To date, there is no consensus regarding the optimal invasive mechanical ventilation strategy for obese surgical patients, and no evidence that possible intraoperative beneficial effects on oxygenation and mechanics translate into better postoperative pulmonary function or improved outcomes. Expert commentary: Before determining the ideal intraoperative ventilation strategy, it is important to analyze the pathophysiology and comorbidities of each obese patient. Protective ventilation with low tidal volume, driving pressure, energy, and mechanical power should be employed during surgery; however, further studies are required to clarify the most effective ventilation strategies, such as the optimal positive end-expiratory pressure and whether recruitment maneuvers minimize lung injury. In this context, an ongoing trial of intraoperative ventilation in obese patients (PROBESE) should help determine the mechanical ventilation strategy that best improves clinical outcome in patients with body mass index≥35kg/m2.

Dasatinib Reduces Lung Inflammation and Fibrosis in Acute Experimental Silicosis.

Silicosis is an occupational lung disease with no effective treatment. We hypothesized that dasatinib, a tyrosine kinase inhibitor, might exhibit therapeutic efficacy in silica-induced pulmonary fibrosis. Silicosis was induced in C57BL/6 mice by a single intratracheal administration of silica particles, whereas the control group received saline. After 14 days, when the disease was already established, animals were randomly assigned to receive DMSO or dasatinib (1 mg/kg) by oral gavage, twice daily, for 14 days. On day 28, lung morphofunction, inflammation, and remodeling were investigated. RAW 264.7 cells (a macrophage cell line) were incubated with silica particles, followed by treatment or not with dasatinib, and evaluated for macrophage polarization. On day 28, dasatinib improved lung mechanics, increased M2 macrophage counts in lung parenchyma and granuloma, and was associated with reduction of fraction area of granuloma, fraction area of collapsed alveoli, protein levels of tumor necrosis factor-α, interleukin-1ß, transforming growth factor-ß, and reduced neutrophils, M1 macrophages, and collagen fiber content in lung tissue and granuloma in silicotic animals. Additionally, dasatinib reduced expression of iNOS and increased expression of arginase and metalloproteinase-9 in silicotic macrophages. Dasatinib was effective at inducing macrophage polarization toward the M2 phenotype and reducing lung inflammation and fibrosis, thus improving lung mechanics in a murine model of acute silicosis.

Effects of Ilex paraguariensis (yerba mate) treatment on leptin resistance and inflammatory parameters in obese rats primed by early weaning.

AIMS: We evaluated the effects of yerba mate treatment over 30 days on body weight, food intake, hypothalamic leptin action and inflammatory profile in adult rats that were weaned early. MAIN METHODS: To induce early weaning, the teats of lactating rats were blocked with a bandage to interrupt milk access for the last 3 days of lactation (EW group). Control offspring had free access to milk throughout lactation. On postnatal day (PN) 150, EW offspring were subdivided into: EW and M groups were treated with water and mate aqueous solution (1g/kg BW/day, gavage), respectively, for 30 days. Control offspring received water by gavage. On PN180, offspring were killed. KEY FINDINGS: EW group presented hyperphagia; higher adiposity; higher NPY and TNF-α expression in the ARC nucleus; higher TNF-α and IL-1ß levels in the adipose tissue; and lower IL-10 levels in the adipose tissue. These characteristics were normal in M group. As expected, the leptin injection in control offspring caused lower food intake. However, EW group exhibited no change in food intake after the leptin injection, indicating leptin resistance. In contrast, M group had a normal response to the leptin injection. SIGNIFICANCE: Thirty days of mate treatment prevented the development of hyperphagia, overweight, visceral obesity and central leptin resistance. This beneficial effect on the satiety of M offspring most likely occurred after the improvement of inflammatory markers in the hypothalamus and adipocytes, which suggests that Ilex paraguariensis plays an important role in the management of obesity by acting on the inflammatory profile.

Avaliação do metabolismo ósseo em modelos de plasticidade ontogenética / Evaluation of bone metabolism in models of developmental plasticity

O aumento da prevalência da obesidade e osteoporose, bem como a identificação de mecanismos comuns que ligam a osteogênese e a adipogênese, sugerem que a obesidade e osteoporose podem ser distúrbios relacionados, e além disso, ambos podem ter suas origens no início da vida. Em 3 modelos diferentes de plasticidade ontogenética foi observado obesidade na vida adulta. Sendo assim, o objetivo deste trabalho foi investigar o impacto desses 3 modelos, o desmame precoce mecânico (DPM) e o farmacológico (DPF), e a supernutrição neonatal (SN) no tecido ósseo da prole durante o desenvolvimento. Para tanto, 2 experimentos foram realizados. No experimento 1, ratas lactantes foram divididas em 3 grupos: controle - os filhotes tiveram livre acesso ao leite durante toda a lactação; DPM - as mães foram envolvidas com uma atadura nos últimos 3 dias de lactação; DPF - as mães foram tratadas com bromocriptina (0,5 mg/duas vezes/dia) 3 dias antes do desmame padrão. No experimento 2, o tamanho da ninhada foi reduzido para 3 filhotes machos no 3o dia de lactação até o desmame (SN); o grupo controle permaneceu com 10 filhotes durante toda a lactação. Realizou-se absorciometria de raios-x de dupla energia, tomografia computadorizada, microtomografia computadorizada, teste biomecânico e análises séricas. Os dados foram considerados significativos quando P<0,05. No experimento 1, ao desmame, os filhotes DPM e DPF apresentaram menor massa corporal, massa gorda, densidade mineral óssea total (DMO), conteúdo mineral ósseo total (CMO), área óssea e osteocalcina sérica, e maior telopeptídeo carboxi-terminal do colágeno tipo I (CTX-I). O cálcio ionizado sérico foi menor apenas na prole DPM, a 25-hidroxivitamina D (25(OH)D) foi maior e o PTH menor apenas na prole DPF. Aos 180 dias, as proles DPM e DPF apresentaram maior massa corporal, maior massa de gordura visceral, hiperleptinemia, maior 25(OH)D e menor CTX-I...

Nutritional changes during critical developmental periods are associated with chronic diseases in adulthood, a phenomenon known as developmental plasticity. Osteogenesis and adipogenesis have common mechanisms. In 3 different models of developmental plasticity, we observed programming for obesity. Thus, the aim of this study was to investigate the impact of these 3 models, mechanical early weaning (MEW), pharmacological early weaning (PEW), and early overnutrition (EO) upon offspring’s bone tissue during development. Thus, the present study was divided into two experiments. In experiment 1, lactating rats were separated into 3 groups: control - pups had free access to milk; MEW - dams were involved with a bandage interrupting lactation in the last 3 days; PEW - dams were pharmacologically treated to block prolactin (0.5 mg bromocryptine/twice a day) 3 days before standard weaning. In experiment 2, litter size was adjusted to 3 male rats per litter (EO). Litter containing 10 pups per mother was control. Bone tissue was evaluated by dual-energy X-ray absorptiometry, computed tomography, microcomputed tomography, biomechanical tests and serum analyses. Data significant had P<0.05. In experiment 1, at weaning, MEW and PEW pups presented lower body weight, total body fat, total bone mineral density (BMD), total bone mineral content (BMC), bone area, serum osteocalcin and higher C-terminal cross-linked telopeptide of type I collagen (CTX-I). However, serum ionized calcium was lower only in MEW pups, 25-hydroxyvitamin D was higher and PTH was lower only in PEW pups. In adulthood, MEW and PEW groups presented higher body weight, visceral fat mass, 25-hydroxivitamin D, hyperleptinemia and lower CTX-I...