Beneficial effects of Ilex paraguariensis in the prevention of obesity-associated metabolic disorders in mice.

Obesity is a chronic condition involving inflammation and oxidative stress that commonly predisposes affected individuals to develop metabolic disorders. We hypothesize that Ilex paraguariensis (IP) can modulate oxidative stress and inflammation underpinning metabolic disorders caused by obesity. C57BL/6 mice were fed a high-fat diet (HFD group) for 12 weeks. Concomitantly, some mice were treated with roasted IP (15 mg/ml - HFD + IP) or dimethyl fumarate (DMF) as a positive control (2 mg/ml - HFD + DMF). The control group received standard chow and water ad libitum. Histological analyses of fat tissue and liver, and quantification of mediators related to oxidative stress (Kelch-like ECH-associated protein 1/NF-E2-related factor 2, NADP(H) quinone oxidoreductase-1 [NQO1], heme oxygenase 1 [HO1], and superoxide dismutase) as well as metabolic profile blood biomarkers (glucose, leptin, resistin, high-density lipoproteins [HDLs], and triglycerides) were performed. Metabolic disorders were prevented in mice treated with IP, as evidenced by the observation that glucose, HDL, and resistin levels were similar to those assessed in the control group. Morphological analyses showed that both IP and DMF treatments prevented hepatic steatosis and adipocyte hypertrophy in visceral adipose tissue. Finally, although the antioxidant response stimulated by IP was quite limited, significant effects were found on NQO1 and HO1 expression. In conclusion, IP has promising preventative effects on the development of metabolic disorders caused by obesity.

Diallyl disulfide prevents cigarette smoke-induced emphysema in mice.

INTRODUCTION: Cigarette smoke (CS) is the main risk factor for the development of chronic obstructive pulmonary disease (COPD) and pulmonary emphysema. The use of antioxidants has emerged as a potential therapeutic strategy to treat airway inflammation and lung diseases. In the current study, we investigated the potential therapeutic impact of diallyl disulfide (Dads) treatment in a murine model of CS-induced emphysema. METHODS: C57BL/6 mice were exposed to CS for 60 consecutive days and treated with vehicle or Dads (30, 60 or 90 mg/kg) by oral gavage for the last 30 days, three times/week. The control group was sham-smoked and received vehicle treatment. All mice were euthanized 24 h after day 60; bronchoalveolar lavage (BAL) was performed and lungs were processed for further experimentation. Histological (HE stained sections, assessment of mean linear intercept (Lm)), biochemical (nitrite, superoxide dismutase (SOD), glutathione transferase (GST), and malondialdehyde (MDA) equivalents), and molecular biology (metalloproteinase (MMP) 12, SOD2, carbonyl reductase 1 (CBR1), nitrotyrosine (PNK), 4-hydroxynonenal (4-HNE), and CYP2E1) analyses were performed. RESULTS: Treatment with Dads dose-dependently reduced CS-induced leukocyte infiltration into the airways (based on BAL fluid counts) and improved lung histology (indicated by a reduction of Lm). Furthermore, CS exposure dramatically reduced the activity of the antioxidant enzymes SOD and GST in lung tissue and increased nitrite and MDA levels in BAL; these effects were all effectively counteracted by Dads treatment. Western blot analysis further confirmed the antioxidant potential of Dads, showing that treatment prevented the CS-induced decrease in SOD2 expression and increase in lung damage markers, such as CBR1, PNK, and 4-HNE. Furthermore, increased MMP12 (an important hallmark of CS-induced emphysema) and CYP2E1 lung protein levels were significantly reduced in mice receiving Dads treatment. CONCLUSION: Our findings demonstrate that treatment with Dads is effective in preventing multiple pathological features of CS-induced emphysema in an in vivo mouse model. In addition, we have identified several proteins/enzymes, including 4-HNE, CBR1, and CYP2E1, that are modifiable by Dads and could represent specific therapeutic targets for the treatment of COPD and emphysema.

Propolis reversed cigarette smoke-induced emphysema through macrophage alternative activation independent of Nrf2.

Chronic obstructive pulmonary disease (COPD) is an incurable and progressive disease. Emphysema is the principal manifestation of COPD, and the main cause of this condition is cigarette smoke (CS). Natural products have shown antioxidant and anti-inflammatory properties that can prevent acute lung inflammation and emphysema, but there are few reports in the literature regarding therapeutic approaches to emphysema. We hypothesized that supplementation with natural extracts would repair lung damage in emphysema caused by CS exposure. Mice were exposed to 60days of CS and then treated or not with three different natural extracts (mate tea, grape and propolis) orally for additional 60days. Histological analysis revealed significant improvements in lung histoarchitecture, with recovery of alveolar spaces in all groups treated with natural extracts. Propolis was also able to recovery alveolar septa and elastic fibers. Propolis also increased MMP-2 and decreased MMP-12 expression, favoring the process of tissue repair. Additionally, propolis recruited leukocytes, including macrophages, without ROS release. These findings led us to investigate the profile of these macrophages, and we showed that propolis could promote macrophage alternative activation, thus increasing the number of arginase-positive cells and IL-10 levels and favoring an anti-inflammatory microenvironment. We further investigated the participation of Nrf2 in lung repair, but no Nrf2 translocation to the nucleus was observed in lung cells. Proteins and enzymes related to Nrf2 were not altered, other than NQO1, which seemed to be activated by propolis in a Nrf2-independent manner. Finally, propolis downregulated IGF1 expression. In conclusion, propolis promoted lung repair in a mouse emphysema model via macrophage polarization from M1 to M2 in parallel to the downregulation of IGF1 expression in a Nrf2-independent manner.

Eucalyptol attenuates cigarette smoke-induced acute lung inflammation and oxidative stress in the mouse.

Short-term cigarette smoke (CS) exposure does not cause emphysema; however, some pathogenesis hallmarks are maintained, such as oxidative stress and inflammation. This study aimed to test the efficacy of eucalyptol against short-term CS exposure in mice. C57BL/6 mice were exposed to 12 cigarettes per day for 5 days (CS group). The control group was exposed to sham smoking. Three groups of mice exposed to CS were treated to different concentrations of eucalyptol (1, 3, 10 mg/mL) via inhalation (15 min/daily) for 5 days (CS + 1 mg, CS+3 mg and CS+10 mg groups). CS group and control one were sham treated by using vehicle. The anti-inflammatory and antioxidant effects of eucalyptol were assessed 24 h after the last CS exposure by determining cell counts, measuring cytokine production and performing western blotting, biochemical and histological analyses. Eucalyptol at 3 mg/mL and 10 mg/mL concentrations reduced total leukocyte numbers compared to the CS group (p < 0.001), while macrophage numbers were reduced at all concentrations (p < 0.001). Myeloperoxidase, used as neutrophil marker, was reduced at 3 mg/mL (p < 0.01) and 10 mg/mL (p < 0.05) concentrations. Eucalyptol reduced cytokine levels (IL-1ß, IL-6 and KC) at 3 mg/mL and 10 mg/mL concentrations (p < 0.01) compared to the CS group. The exception was TNF-α, with a reduction only at 10 mg/mL of eucalyptol compared to the CS group (p < 0.001). Additionally, eucalyptol decreased the NF-kappa B p65 subunit at 3 mg/mL and 10 mg/mL compared to the CS group (p < 0.01). Regarding oxidative stress, eucalyptol reduced reactive oxygen species, superoxide dismutase, catalase and malondialdehyde, mainly at 3 mg/mL and 10 mg/mL concentrations compared to the CS group (at least p < 0.05), parallel to reduced glutathione levels at the same concentrations (p < 0.001). Furthermore, treatment with eucalyptol attenuated CS-induced histopathological alterations. Collectively, these results indicate that eucalyptol acts through a mechanism involving decreased oxidative stress, inflammation and the NF-kappa B p65 subunit against CS-induced acute lung inflammation. Thus, eucalyptol may be a potential agent in the treatment of pulmonary inflammation caused by CS in humans.

Critical role for CCR2 and HMGB1 in induction of experimental endotoxic shock.

Our aim was to investigate CCR2 and HMGB1 involvement in a murine model of endotoxic shock. We used C57BL/6 CCR2 knockout (KO) mice and wild-type (WT) littermates to establish an optimal dose of LPS. CCR2 KO mice survived more frequently than WT mice after 80, 40 and 20 mg/kg of LPS i.p. Inflammation and redox markers were high in WT mice than in CCR2 KO mice. HMGB1 expression was reduced in CCR2 KO mice in parallel to ERK 1/2 activation. Therefore, we used glycyrrhizic acid (50 mg/kg), an HMGB1 inhibitor in WT mice injected with LPS, and mortality was fully abolished. Thus, drugs targeting CCR2 and HMGB1 could represent future resources for sepsis treatment.

Antioxidant action of propolis on mouse lungs exposed to short-term cigarette smoke.

Propolis is a natural product with antioxidant properties. In this study, we tested the efficacy of propolis against acute lung inflammation (ALI) caused by cigarette smoke (CS). C57BL6 male mice were exposed to CS and treated with propolis (200mg/kg orally, CS+P) or only with propolis (P). A Control group treated with propolis was sham-smoked (Control+P). We collected the lungs for histological and biochemical analyses. We observed an increase in alveolar macrophages and neutrophils in the CS group compared with the Control+P. These counts reduced in the CS+P group compared to the CS group. The treatment with propolis normalized all biochemical parameters in the CS+P group compared with the CS group, including nitrite, myeloperoxidase level, antioxidant enzyme activities (superoxide dismutase, catalase and glutathione peroxidase), reduced glutathione/oxidized glutathione ratio and malondialdehyde. Additionally, TNF-α expression reduced in the CS+P group when compared with the CS group. These data imply a potential antioxidant and anti-inflammatory role for propolis with regard to ALI caused by CS in mice.

Oxidative Stress and Inflammation in Acute and Chronic Lung Injuries.

Acute and chronic lung injuries are among the leading causes of mortality worldwide. Lung injury can affect several components of the respiratory system, including the airways, parenchyma, and pulmonary vasculature. Although acute and chronic lung injuries represent an enormous economic and clinical burden, currently available therapies primarily focus on alleviating disease symptoms rather than reversing and/or preventing lung pathology. Moreover, some supportive interventions, such as oxygen and mechanical ventilation, can lead to (further) deterioration of lung function and even the development of permanent injuries. Lastly, sepsis, which can originate extrapulmonary or in the respiratory system itself, contributes to many cases of lung-associated deaths. Considering these challenges, we aim to summarize molecular and cellular mechanisms, with a particular focus on airway inflammation and oxidative stress that lead to the characteristic pathophysiology of acute and chronic lung injuries. In addition, we will highlight the limitations of current therapeutic strategies and explore new antioxidant-based drug options that could potentially be effective in managing acute and chronic lung injuries.

Modulation of Alveolar Macrophage Activity by Eugenol Attenuates Cigarette-Smoke-Induced Acute Lung Injury in Mice.

This study investigates the role of eugenol (EUG) on CS-induced acute lung injury (ALI) and how this compound is able to modulate macrophage activity. C57BL/6 mice were exposed to 12 cigarettes/day/5days and treated 15 min/day/5days with EUG. Rat alveolar macrophages (RAMs) were exposed to CSE (5%) and treated with EUG. In vivo, EUG reduced morphological changes inflammatory cells, oxidative stress markers, while, in vitro, it induced balance in the oxidative stress and reduced the pro-inflammatory cytokine release while increasing the anti-inflammatory one. These results suggest that eugenol reduced CS-induced ALI and acted as a modulator of macrophage activity.

Time course of inflammation, oxidative stress and tissue damage induced by hyperoxia in mouse lungs.

In this study our aim was to investigate the time courses of inflammation, oxidative stress and tissue damage after hyperoxia in the mouse lung. Groups of BALB/c mice were exposed to 100% oxygen in a chamber for 12, 24 or 48 h. The controls were subjected to normoxia. The results showed that IL-6 increased progressively after 12 (P < 0.001) and 24 h (P < 0.001) of hyperoxia with a reduction at 48 h (P < 0.01), whereas TNF-α increased after 24 (P < 0.001) and 48 h (P < 0.001). The number of macrophages increased after 24 h (P < 0.001), whereas the number of neutrophils increased after 24 h (P < 0.01) and 48 h (P < 0.001). Superoxide dismutase activity decreased in all groups exposed to hyperoxia (P < 0.01). Catalase activity increased only at 48 h (P < 0.001). The reduced glutathione/oxidized glutathione ratio decreased after 12 h (P < 0.01) and 24 h (P < 0.05). Histological evidence of lung injury was observed at 24 and 48 h. This study shows that hyperoxia initially causes an inflammatory response at 12 h, resulting in inflammation associated with the oxidative response at 24 h and culminating in histological damage at 48 h. Knowledge of the time course of inflammation and oxidative stress prior to histological evidence of acute lung injury can improve the safety of oxygen therapy in patients.

Treatment with Bixin-Loaded Polymeric Nanoparticles Prevents Cigarette Smoke-Induced Acute Lung Inflammation and Oxidative Stress in Mice.

The use of annatto pigments has been evaluated as a therapeutic strategy in animal models of several health disorders. Beneficial effects were generally attributed to the inhibition of oxidative stress. Bixin is the main pigment present in annatto seeds and has emerged as an important scavenger of reactive oxygen (ROS) and nitrogen species (RNS). However, this carotenoid is highly hydrophobic, affecting its therapeutic applicability. Therefore, bixin represents an attractive target for nanotechnology to improve its pharmacokinetic parameters. In this study, we prepared bixin nanoparticles (npBX) and evaluated if they could prevent pulmonary inflammation and oxidative stress induced by cigarette smoke (CS). C57BL/6 mice were exposed to CS and treated daily (by gavage) with different concentrations of npBX (6, 12 and 18%) or blank nanoparticles (npBL, 18%). The negative control group was sham smoked and received 18% npBL. On day 6, the animals were euthanized, and bronchoalveolar lavage fluid (BALF), as well as lungs, were collected for analysis. CS exposure led to an increase in ROS and nitrite production, which was absent in animals treated with npBX. In addition, npBX treatment significantly reduced leukocyte numbers and TNF-α levels in the BALF of CS-exposed mice, and it strongly inhibited CS-induced increases in MDA and PNK in lung homogenates. Interestingly, npBX protective effects against oxidative stress seemed not to act via Nrf2 activation in the CS + npBX 18% group. In conclusion, npBX prevented oxidative stress and acute lung inflammation in a murine model of CS-induced acute lung inflammation.

Gold Nanoparticles Inhibit Steroid-Insensitive Asthma in Mice Preserving Histone Deacetylase 2 and NRF2 Pathways.

BACKGROUND: Gold nanoparticles (AuNPs) can inhibit pivotal pathological changes in experimental asthma, but their effect on steroid-insensitive asthma is unclear. The current study assessed the effectiveness of nebulized AuNPs in a murine model of glucocorticoid (GC)-resistant asthma. METHODS: A/J mice were sensitized and subjected to intranasal instillations of ovalbumin (OVA) once a week for nine weeks. Two weeks after starting allergen stimulations, mice were subjected to Budesonide or AuNP nebulization 1 h before stimuli. Analyses were carried out 24 h after the last provocation. RESULTS: We found that mice challenged with OVA had airway hyperreactivity, eosinophil, and neutrophil infiltrates in the lung, concomitantly with peribronchiolar fibrosis, mucus production, and pro-inflammatory cytokine generation compared to sham-challenged mice. These changes were inhibited in mice treated with AuNPs, but not Budesonide. In the GC-resistant asthmatic mice, oxidative stress was established, marked by a reduction in nuclear factor erythroid 2-related factor 2 (NRF2) levels and catalase activity, accompanied by elevated values of thiobarbituric acid reactive substances (TBARS), phosphoinositide 3-kinases δ (PI3Kδ) expression, as well as a reduction in the nuclear expression of histone deacetylase 2 (HDAC2) in the lung tissue, all of which sensitive to AuNPs but not Budesonide treatment. CONCLUSION: These findings suggest that AuNPs can improve GC-insensitive asthma by preserving HDAC2 and NRF2.

Mate tea ameliorates emphysema in cigarette smoke-exposed mice.

Exposure to cigarette smoke (CS) is associated with lung inflammation, oxidative stress, and emphysema. The aim of this work was to study Mate tea as a possible natural antioxidant resource against emphysema development. C57BL/6 mice were distributed into 4 groups: exposed to ambient air (control), exposed to the smoke of 12 cigarettes (CS), exposed to ambient air and treated with Mate (500 mg/kg/day diluted in 100 µL) (Mate), and exposed to CS and treated with Mate (CS+Mate). All mice were treated for 60 days. On day 61 the mice were killed. Right and left lungs were removed for histology and biochemical analysis, respectively. Emphysematous lesions and inflammatory cell influxes in the CS group were evident by histological analysis. Cells showed higher 4-hydroxynonenal labeling in the CS group than in the CS+Mate group. Myeloperoxidase activity was reduced in the CS+Mate group compared to the CS group. Superoxide dismutase and catalase activities were significantly higher in the CS+Mate group compared to the CS group. The ratio of reduced to oxidized glutathione was greater in the CS+Mate group than in the CS group. CS-induced emphysema in C57BL/6 mice was prevented by Mate in association with a reduction in inflammatory and oxidative stress parameters.

Dietary citrate acutely induces insulin resistance and markers of liver inflammation in mice.

Citrate is widely used as a food additive being part of virtually all processed foods. Although considered inert by most of the regulatory agencies in the world, plasma citrate has been proposed to play immunometabolic functions in multiple tissues through altering a plethora of cellular pathways. Here, we used a short-term alimentary intervention (24 hours) with standard chow supplemented with citrate in amount corresponding to that found in processed foods to evaluate its effects on glucose homeostasis and liver physiology in C57BL/6J mice. Animals supplemented with dietary citrate showed glucose intolerance and insulin resistance as revealed by glucose and insulin tolerance tests. Moreover, animals supplemented with citrate in their food displayed fed and fasted hyperinsulinemia and enhanced insulin secretion during an oral glucose tolerance test. Citrate treatment also amplified glucose-induced insulin secretion in vitro in INS1-E cells. Citrate supplemented animals had increased liver PKCα activity and altered phosphorylation at serine or threonine residues of components of insulin signaling including IRS-1, Akt, GSK-3 and FoxO1. Furthermore, citrate supplementation enhanced the hepatic expression of lipogenic genes suggesting increased de novo lipogenesis, a finding that was reproduced after citrate treatment of hepatic FAO cells. Finally, liver inflammation markers were higher in citrate supplemented animals. Overall, the results demonstrate that dietary citrate supplementation in mice causes hyperinsulinemia and insulin resistance both in vivo and in vitro, and therefore call for a note of caution on the use of citrate as a food additive given its potential role in metabolic dysregulation.

Organ-related cigarette smoke-induced oxidative stress is strain-dependent.

BACKGROUND: Cigarette smoke (CS) is associated with oxidative stress in several organs because it contains high concentrations of free radicals and reactive oxygen species. Experimental models, using different strains, provide important insights into the genetic basis of diseases. This study sought to identify, in different mouse strains, the organ that is most-susceptible to CS-induced oxidative stress to obtain an optimized experimental animal model of oxidative injury induced by CS. MATERIAL/METHODS: Male Swiss, DBA/2, C3H, BALB/c, and C57BL/6 mice were exposed to CS 3 times a day (4 cigarettes per session) for 60 consecutive days. Control groups from the same strains were sham-treated. Protein content, malondialdehyde level, myeloperoxidase activity, and nitrite level were assayed in lung, liver, kidney, and brain from all strains. Catalase and glutathione peroxidase activities were measured. Analyses of data were done by using a 1-way ANOVA with Bonferroni's post-test (P<.05). RESULTS: Cigarette smoke exposure resulted in distinct, organ-specific responses among strains. The survival rate of DBA/2 mice was lowest. BALB/c and C57BL/6 strains were more-susceptible to oxidative damage in the lung and liver. C3H and C57BL/6 mice were more-susceptible to oxidative damage in the brain. No renal oxidative damage was seen. CONCLUSIONS: Mouse strains and individual organs display a range of susceptibilities to CS-induced oxidative stress. BALB/c and C57BL/6 strains appear to be the best choices as experimental models for studying CS effects on liver and lung, and C3H and C57BL/6 strains for CS-effects on the brain.

Mate tea reduces high fat diet-induced liver and metabolic disorders in mice.

High-fat diet (HFD)-induced obesity is a worldwide health problem and can cause lipid accumulation in the liver. We evaluated the hepatoprotective effect of mate tea treatment in mice submitted to an HFD. C57BL/6 mice were fed an HFD for 13 weeks with and without mate tea. A separate group of mice was treated with fenofibrate as a positive control (a regular drug for lipid disorders). Histological analyses, glucose tolerance tests (GTT), and quantification of mediators related to lipid peroxidation, oxidative stress and blood biomarkers for lipid profile were performed. The weight of animals and major organs related to hepatic steatosis was determined, and proinflammatory cytokines and the participation of the Nrf2 pathway and adiponectin were evaluated. Mate tea prevented the accumulation of lipid droplets in hepatocytes as well as weight gain in animals submitted to the HFD. Mate tea treatment also prevented increases in the liver weight, heart weight and amount of visceral and subcutaneous white adipose tissue. Mate tea was able to prevent the deregulation of glucose uptake, as evaluated by GTT, and improved the indicators of oxidative stress, such as nitrite levels, catalase activity, and oxidative damage, as evaluated by protein carbonylation and the MDA levels. Mate tea had an anti-inflammatory effect, preventing the increase of IL-1ß and KC and upregulating the expression of Nrf2. Mate tea prevented insulin increase and HDL cholesterol decrease but did not affect total cholesterol or triglycerides levels. Treatment also prevented adiponectin increase. Mate tea may be a good resource to reduce hepatic steatosis in the future since it has anti-diabetic, anti-inflammatory and antioxidant effects, which prevent the accumulation of fat in the liver.

Acute Exposure to Diesel-Biodiesel Particulate Matter Promotes Murine Lung Oxidative Stress by Nrf2/HO-1 and Inflammation Through the NF-kB/TNF-α Pathways.

Air pollution caused by fuel burning contributes to respiratory impairments that may lead to death. We aimed to investigate the effects of biodiesel (DB) burning in mouse lungs. DB particulate matter was collected from the exhaust pipes of a bus engine. Mice were treated with 250 µg or 1000 µg of DB particulate matter by intranasal instillation over 5 consecutive days. We demonstrated that DB particulate matter penetrated the lung in the 250-µg and 1000-µg groups. In addition, the DB particulate matter number in pulmonary parenchyma was 175-fold higher in the 250-µg group and 300-fold higher in the 1000-µg group compared to control mice. The instillation of DB particulate matter increased the macrophage number and protein levels of TNF-alpha in murine lungs. DB particulate matter enhanced ROS production in both exposed groups and the malondialdehyde levels compared to the control group. The protein expression levels of Nrf2, p-NF-kB, and HO-1 were higher in the 250-µg group and lower in the 1000-µg group than in control mice and the 250-µg group. In conclusion, DB particulate matter instillation promotes oxidative stress by activating the Nrf2/HO-1 and inflammation by p-NF-kB/TNF-alpha pathways.

Probiotic Prato cheese attenuates cigarette smoke-induced injuries in mice.

The efficacy of probiotic Prato cheese against the inflammatory and oxidative damage in mice organs induced by cigarette smoke exposure was investigated. Forty C57BL/6 male mice were assigned to four groups: (CS) exposed to cigarette smoke and fed regular chow; (CS + C) exposed to cigarette smoke and fed daily conventional cheese ad libitum; (CS + PC) exposed to cigarette smoke and fed daily probiotic (Lactobacillus casei-01) cheese ad libitum; and a control group (C) exposed to ambient smoke-free air and fed regular chow. Bronchoalveolar lavage (BAL), blood, gut and liver homogenates were used for biochemical assays. The (CS + PC) group exhibited fewer BAL leukocytes, reactive oxygen species (ROS), and BAL and gut lipid peroxidation than the (CS) and (CS + C) groups, which had findings similar to the (C) group. Probiotic cheese consumption did not change the red blood cell count, but lower lactate dehydrogenase (LDH) levels in plasma, inducible nitric oxide synthase (iNOS) and peroxynitrite expression were observed compared to the (CS) and (CS + C) groups, with findings similar to the (C) group. These results suggest that probiotic Prato cheese consumption reduced oxidative stress in the lungs, gut, and liver.

Mate tea reduced acute lung inflammation in mice exposed to cigarette smoke.

OBJECTIVE: Short-term cigarette smoke exposure has been associated with acute lung inflammation (ALI) and oxidative damage. We studied mate tea (Ilex paraguariensis infusion) as a possible nutritional resource for ALI. METHODS: C57BL/6 mice (n = 30) were administered with mate tea orally (150 mg/kg, CSMO), mate tea intraperitonially (150 mg/kg, CSMIP), or the vehicle (CS) and then exposed to cigarette smoke for 5 d (six cigarettes per day). The control group was sham-smoked (n = 30). One day after the final exposure, mice were sacrificed. Bronchoalveolar lavages were performed and lungs removed for biochemical (lung homogenates) and histologic analyses. RESULTS: Mate tea reduced the increase of alveolar macrophages and neutrophils in bronchoalveolar lavages (cells x 10(3)/mL) of the CSMO (214.3 +/- 21.4 and 12.2 +/- 4.9) and CSMIP (248.3 +/- 11.1 and 12.1 +/- 2.3) groups compared with the CS group (425.9 +/- 28.1 and 140.5 +/- 20.1). Mate tea reduced lipid peroxidation (the control group was considered 100%) and tumor necrosis factor-alpha (picograms per milliliter) in the CSMO group (61.3 +/- 11.3 and 185.3 +/- 21.8) compared with the CS group (150.0 +/- 18.1 and 242.3 +/- 13.2). Matrix metalloprotease-9 activity was higher in the CS group and lower in the CSMO group. Oxidative and inflammatory markers in the CSMO group were not different from those in the control group. CONCLUSION: These data imply a potential antioxidant role for mate tea on ALI. Further studies are needed to determine such mechanisms and to explore its potential as an anti-inflammatory and nutritional resource in lung damaged by cigarette smoke exposure.

Atorvastatin dose-dependently promotes mouse lung repair after emphysema induced by elastase.

Emphysema results in a proteinase - antiproteinase imbalance, inflammation and oxidative stress. Our objective was to investigate whether atorvastatin could repair mouse lungs after elastase-induced emphysema. Vehicle (50 µL) or porcine pancreatic elastase (PPE) was administered on day 1, 3, 5 and 7 at 0.6 U intranasally. Male mice were divided into a control group (sham), PPE 32d (sacrificed 24 h after 32 days), PPE 64d (sacrificed 24 h after 64 days), and atorvastatin 1, 5 and 20 mg treated from day 33 until day 64 and sacrificed 24 h later (A1 mg, A5 mg and A20 mg, respectively). Treatment with atorvastatin was performed via inhalation for 10 min once a day. We observed that emphysema at day 32 was similar to emphysema at day 64. The mean airspace chord length (Lm) indicated a recovery of pulmonary morphology in groups A5 mg and A20 mg, as well as recovery of collagen and elastic fibers in comparison to the PPE group. Bronchoalveolar lavage fluid (BALF) leukocytes were reduced in all atorvastatin-treated groups. However, tissue macrophages were reduced only in the A20 mg group compared with the PPE group, while tissue neutrophils were reduced in the A5 mg and A20 mg groups. The redox balance was restored mainly in the A20 mg group compared with the PPE group. Finally, atorvastatin at doses of 5 and 20 mg reduced nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and matrix metalloproteinase-12 (MMP-12) compared with the PPE group. In conclusion, atorvastatin was able to induce lung tissue repair in emphysematous mice.

AT-RVD1 repairs mouse lung after cigarette smoke-induced emphysema via downregulation of oxidative stress by NRF2/KEAP1 pathway.

Long-term exposure to cigarette smoke (CS) results in alveolar parenchyma destruction due to chronic inflammatory response and the imbalance between oxidants and antioxidants, and proteases and antiproteases. Emphysema is the main symptom of chronic obstructive pulmonary disease. Current treatment focuses on relieving respiratory symptoms, and inflammation resolution failure is an important pathophysiological element of the disease. Specialized pro-resolving mediators (SPMs) synthesized endogenously during resolution processes demonstrated beneficial effects in murine models of airway inflammation. Here, we aimed to test the SPM AT-RvD1 in a murine model of CS-induced emphysema. AT-RvD1 restored elastic fibers and lung morphology, with reduction in MMP-3, neutrophils, and myeloperoxidase activity and increases in macrophages and IL-10 levels. AT-RvD1 also decreased levels of oxidative stress markers and ROS via upregulation of the Nrf2/Keap1 pathway. Therefore, we suggest that AT-RvD1 causes pro-resolutive action in our murine model of CS-induced emphysema by upregulation of the Nrf2/Keap1 pathway.