Clarice Rosa Olivo

N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation

Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the α-subunit of the epithelial sodium channel (α-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, α-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.

Anti-inflammatory effects of aerobic exercise in mice exposed to air pollution.

PURPOSE Exposure to diesel exhaust particles (DEP) results in lung inflammation. Regular aerobic exercise improves the inflammatory status in different pulmonary diseases. However, the effects of long-term aerobic exercise on the pulmonary response to DEP have not been investigated. The present study evaluated the effect of aerobic conditioning on the pulmonary inflammatory and oxidative responses of mice exposed to DEP. METHODS BALB/c mice were subjected to aerobic exercise five times per week for 5 wk, concomitantly with exposure to DEP (3 mg·mL(-1); 10 μL per mouse). The levels of exhaled nitric oxide, reactive oxygen species, cellularity, interleukin 6 (IL-6), and tumor necrosis factor α (TNF-α) were analyzed in bronchoalveolar lavage fluid, and the density of neutrophils and the volume proportion of collagen fibers were measured in the lung parenchyma. The cellular density of leukocytes expressing IL-1β, keratinocyte chemoattractant (KC), and TNF-α in lung parenchyma was evaluated with immunohistochemistry. The levels of IL-1β, KC, and TNF-α were also evaluated in the serum. RESULTS Aerobic exercise inhibited the DEP-induced increase in the levels of reactive oxygen species (P < 0.05); exhaled nitric oxide (P < 0.01); total (P < 0.01) and differential cells (P < 0.01); IL-6 and TNF-α levels in bronchoalveolar lavage fluid (P < 0.05); the level of neutrophils (P < 0.001); collagen density in the lung parenchyma (P < 0.05); the levels of IL-6, KC, and TNF-α in plasma (P < 0.05); and the expression of IL-1β, KC, and TNF-α by leukocytes in the lung parenchyma (P < 0.01). CONCLUSIONS We conclude that long-term aerobic exercise presents protective effects in a mouse model of DEP-induced lung inflammation. Our results indicate a need for human studies that evaluate the pulmonary responses to aerobic exercise chronically performed in polluted areas.

Low-Intensity Swimming Training Partially Inhibits Lipopolysaccharide-Induced Acute Lung Injury

BACKGROUND Aerobic exercise decreases pulmonary inflammation and remodeling in experimental models of allergic asthma. However, the effects of aerobic exercise on pulmonary inflammation of nonallergic origin, such as in experimental models of acute lung injury induced by lipopolysaccharide (LPS), have not been evaluated. OBJECTIVE The present study evaluated the effects of aerobic exercise in a model of LPS-induced acute lung injury. METHODS BALB/c mice were divided into four groups: Control, Aerobic Exercise, LPS, and Aerobic Exercise + LPS. Swimming tests were conducted at baseline and at 3 and 6 wk. Low-intensity swimming training was performed for 6 wk, four times per week, 60 min per session. Intranasal LPS (1 mg x kg(-1) (60 microg per mouse)) was instilled 24 h after the last swimming physical test in the LPS and Aerobic Exercise + LPS mice, and the animals were studied 24 h after LPS instillation. Exhaled nitric oxide, respiratory mechanics, total and differential cell counts in bronchoalveolar lavage, and lung parenchymal inflammation and remodeling were evaluated. RESULTS LPS instillation resulted in increased levels of exhaled nitric oxide (P < 0.001), higher numbers of neutrophils in the bronchoalveolar lavage (P < 0.001) and in the lung parenchyma (P < 0.001), and decreased lung tissue resistance (P < 0.05) and volume proportion of elastic fibers (P < 0.01) compared with the Control group. Swim training in LPS-instilled animals resulted in significantly lower exhaled nitric oxide levels (P < 0.001) and fewer neutrophils in the bronchoalveolar lavage (P < 0.001) and the lung parenchyma (P < 0.01) compared with the LPS group. CONCLUSIONS These results suggest that low-intensity swimming training inhibits lung neutrophilic inflammation, but not remodeling and impaired lung mechanics, in a model of LPS-induced acute lung injury.

Effects of aerobic exercise on chronic allergic airway inflammation and remodeling in guinea pigs

We evaluated the effects of aerobic exercise (AE) on airway inflammation, exhaled nitric oxide levels (ENO), airway remodeling, and the expression of Th1, Th2 and regulatory cytokines in a guinea pig asthma model. Animals were divided into 4 groups: non-trained and non-sensitized (C), non-sensitized and AE (AE), ovalbumin-sensitized and non-trained (OVA), and OVA-sensitized and AE (OVA+AE). OVA inhalation was performed for 8 weeks, and AE was conducted for 6 weeks beginning in the 3rd week of OVA sensitization. Compared to the other groups, the OVA+AE group had a reduced density of eosinophils and lymphocytes, reduced expression of interleukin (IL)-4 and IL-13 and an increase in epithelium thickness (p<0.05). AE did not modify airway remodeling or ENO in the sensitized groups (p>0.05). Neither OVA nor AE resulted in differences in the expression of IL-2, IFN-γ, IL-10 or IL1-ra. Our results show that AE reduces the expression of Th2 cytokines and allergic airway inflammation and induces epithelium remodeling in sensitized guinea pigs.

Respiratory mechanics do not always mirror pulmonary histological changes in emphysema

OBJECTIVE : To verify the accordance of functional and morphometric parameters during the development of emphysema. METHODS : BALB/c mice received a nasal drop of either papain or saline solution and were studied after 1, 3, 15, 28, and 40 days. Functional parameters, such as airway resistance, tissue damping, and tissue elastance, were analyzed. To evaluate the structural changes and possible mechanisms involved in this disease, we measured the mean linear intercept, the volume proportions of elastic and collagen fibers, the number of macrophages, the numbers of cells expressing metalloprotease 12 and 8-isoprostane in lung parenchyma. RESULTS : We only observed decreases in tissue elastance and tissue damping on the 28th day, with a concomitant increase in the mean linear intercept, indicating the presence of emphysema. However, only the mean linear intercept values remained increased until the 40th day. The volume proportion of collagen fibers was increased from the 15th day to the 40th day, whereas the volume proportion of elastic fibers was only increased on the 40th day. The number of macrophages increased beginning on the 1st day. The expression of metalloproteinase 12 was increased from the 3rd day until the 40th day. However, 8-isoprostane expression was only increased on the 1st and 3rd days. CONCLUSIONS : In this study, morphometric parameters were found to be more reliable for detecting the presence of emphysema than the functional parameters measured by respiratory mechanics. Further investigations are necessary to understand how the extracellular matrix remodeling observed in the lung parenchyma could be involved in this process.

Aerobic exercise attenuates pulmonary inflammation induced by Streptococcus pneumoniae

Aerobic exercise has been recognized as a stimulator of the immune system, but its effect on bacterial infection has not been extensively evaluated. We studied whether moderate aerobic exercise training prior to Streptococcus pneumoniae infection influences pulmonary inflammatory responses. BALB/c mice were divided into four groups: Sedentary Untreated (sedentary without infection); Sedentary Infected (sedentary with infection); Trained Untreated (aerobic training without infection); and Trained Infected (aerobic training with infection). Animals underwent aerobic training for 4 wk, and 72 h after last exercise training, animals received a challenge with S. pneumoniae and were evaluated either 12 h or 10 days after instillation. In acute phase, Sedentary Infected group had an increase in respiratory system resistance and elastance; number of neutrophils, lymphocytes, and macrophages in bronchoalveolar lavage fluid (BAL); polymorphonuclear cells in lung parenchyma; and levels of keratinocyte-derived chemokine (KC), tumor necrosis factor-α (TNF-α), and interleukin (IL)-1β (IL-1β) in lung homogenates. Exercise training significantly attenuated the increase in all of these parameters and induced an increase in expression of antioxidant enzymes (CuZnSOD and MnSOD) in lungs. Trained Infected mice had a significant decrease in the number of colony-forming units of pneumococci in the lungs compared with Sedentary Infected animals. Ten days after infection, Trained Infected group exhibited lower numbers of macrophages in BAL, polymorphonuclear cells in lung parenchyma and IL-6 in lung homogenates compared with Sedentary Infected group. Our results suggest a protective effect of moderate exercise training against respiratory infection with S. pneumoniae. This effect is most likely secondary to an effect of exercise on oxidant-antioxidant balance.

The Plant-Derived Bauhinia bauhinioides Kallikrein Proteinase Inhibitor (rBbKI) Attenuates Elastase-Induced Emphysema in Mice

Background. Elastase mediates important oxidative actions during the development of chronic obstructive pulmonary disease (COPD). However, few resources for the inhibition of elastase have been investigated. Our study evaluated the ability of the recombinant plant derived Bauhinia bauhinioides Kallikrein proteinase Inhibitor (rBbKI) to modulate elastase-induced pulmonary inflammation. Methods. C57Bl/6 mice were given intratracheal elastase (ELA group) or saline (SAL group) and were treated intraperitoneally with rBbKI (ELA-rBbKI and SAL-rBbKI groups). At day 28, the following analyses were performed: (I) lung mechanics, (II) exhaled nitric oxide (ENO), (III) bronchoalveolar lavage fluid (BALF), and (IV) lung immunohistochemical staining. Results. In addition to decreasing mechanical alterations and alveolar septum disruption, rBbKI reduced the number of cells in the BALF and decreased the cellular expression of TNF-α, MMP-9, MMP-12, TIMP-1, eNOS, and iNOS in airways and alveolar walls compared with the ELA group. rBbKI decreased the volume proportion of 8-iso-PGF2α, collagen, and elastic fibers in the airways and alveolar walls compared with the ELA group. A reduction in the number of MUC-5-positive cells in the airway walls was also observed. Conclusion. rBbKI reduced elastase-induced pulmonary inflammation and extracellular matrix remodeling. rBbKI may be a potential pharmacological tool for COPD treatment.

Tolerogenic microenvironment in neonatal period induced by maternal immunization with ovalbumin

Maternal immunization with allergens, such as ovalbumin (OVA), can inhibit the development of an allergic response in offspring. The regulatory mechanisms seem to be mediated by maternal antibodies (MatAbs) and factors generated by the maternal-fetal interface. The aim of this study was to verify the pathways of inhibitory Ab transference after maternal immunization with OVA and the effect of the offsprings dendritic cells (DCs) on the generation of regulatory T (Treg) cells. We verified that preconceptional OVA immunization induces high levels of proinflammatory and regulatory cytokines in the amniotic fluid, allowing the transference of high levels of anti-OVA IgG1 Abs to the offspring. Using an adoptive nursing protocol, we verified that maternal immunization leads to MatAb transference by the placental route and by breastfeeding contribute to the inhibition of anaphylactic IgE and IgG1 Ab responses in immunized offspring. We observed that maternal immunization decreased eosinophil numbers in recovered bronchoalveolar lavage fluid and in the lung tissue, whereas with a lack of control of airway responsiveness to methacholine. Maternal immunization induced in young offspring a decreased percentage of CD11c+ DCs expressing MHC class II and CD40 molecules. Moreover, DCs from both groups of offspring when pulsed with OVA, were able to induce Treg cells in vitro. Similarly, OVA immunization at the neonatal stage increased the frequency of Treg cells, regardless of the mothers immunization status. These findings emphasize that maternal immunization leads to a complex interaction of regulatory factors, with MatAbs, DCs and Treg cells affecting the tolerance of offspring during an allergic response.

Exercise reverses OVA-induced inhibition of glucocorticoid receptor and increases anti-inflammatory cytokines in asthma

The purpose of this study was to determine the effect of aerobic exercise training (AT) on the expression of glucocorticoid receptors (GR) and anti‐inflammatory cytokines in an asthma model. BALB/c mice were divided into groups control (CT; nonsensitized/nontrained), aerobic training (AT; nonsensitized/trained), ovalbumin (OVA; sensitized/not trained), and OVA+AT (sensitized/trained). OVA groups received OVA by inhalation, and the AT groups completed 1, 3, or 7 days of exercise (60 min/session). Expression of GR, IL‐4, IL‐5, IL‐10, IL‐1ra, NF‐κB, TGF‐β, VEGF, ICAM‐1, VCAM‐1; eosinophils counting; and airway remodeling (AR) features [airway smooth muscle (ASM) and epithelial thickness and collagen fiber deposition] were quantified. OVA sensitization induced a decrease in the expression of GR and increases in the eosinophil, IL‐4, IL‐5, NF‐κB, TGF‐β, VEGF, ICAM‐1, VCAM‐1, and AR features (P < 0.05). After 3 days, AT reversed the OVA‐induced reduction in the expression of GR, and subsequently induced increases in the expression of IL‐10 and IL‐1ra (seventh day). In contrast, the eosinophil migration, the expression of NF‐κB, IL‐4, IL‐5, TGF‐β, RANTES, VEGF, ICAM‐1, VCAM‐1, and the AR features (P < 0.05) were reduced. AT increases the expression of GR and anti‐inflammatory cytokines (IL‐10 and IL‐1ra) and reduces the expression of inflammatory mediators and airway inflammation in an animal model of asthma.

Airway remodeling is reversed by aerobic training in a murine model of chronic asthma

The aim of this study was to investigate if the aerobic training (AT) reverses airway remodeling (AR) in an asthma model. BALB/c were divided into four groups: control (unsensitized and untrained); ovalbumin (OVA: sensitized and untrained); AT (unsensitized and trained) and OVA + AT. Allergic inflammation was induced with intraperitoneal and OVA inhalation. AT (low intensity; 5×/week; 60 min/session) was performed at 7, 15, and 30 days. Leukocyte counting in the bronchoalveolar lavage fluid; the expression of IL‐5, eotaxin, RANTES, intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1); AR features (airway smooth muscle, epithelium thickness, collagen and elastic fibers, mucus production); and AR inducers (transforming growing factor‐beta, osteopontin, vascular endothelial growth factor). OVA induced an increase in leukocyte airway migration and increased AR features (P < 0.05). After 7 days, AT reversed the OVA‐induced eosinophil and macrophage airway migration, the expression of IL‐5, eotaxin, RANTES, ICAM‐1, VCAM‐1, and all AR inducers. However, total reversion of the AR features and inducers and airway inflammation occurred only after 15 days of AT compared with the OVA groups (P < 0.05) and the effects were maintained until the 30th day. AT reverses AR after 15 days and this effect is preceded by the inhibition of leukocyte migration and occurs simultaneously with the reduction in the expression of inflammatory mediators and AR inducers.