Carla Prado | UNIFESP - Academia.edu (original) (raw)

Papers by Carla Prado

PloS one, 2014

To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in m... more To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in mice. C57BL/6 mice were subjected to porcine pancreatic elastase (PPE) nasal instillation to induce emphysema and were treated with a serine protease inhibitor (rBmTI-A) before (Protocol 1) and after (Protocol 2) emphysema development. In both protocols, we evaluated lung function to evaluate the airway resistance (Raw), tissue damping (Gtis) and tissue elastance (Htis). The inflammatory profile was analyzed in the bronchoalveolar lavage (BALF) and through the use of morphometry; we measured the mean linear intercept (Lm) (to verify alveolar enlargement), the volume proportion of collagen and elastic fibers, and the numbers of macrophages and metalloprotease 12 (MMP-12) positive cells in the parenchyma. We showed that at both time points, even after the emphysema was established, the rBmTI-A treatment was sufficient to reverse the loss of elastic recoil measured by Htis, the alveolar enla...

Respiratory Research, 2015

Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative... more Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema. Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2α and p65-NF-κB in the fixed tissues as well as to evaluate cytokine levels and p65-NF-κB protein expression. In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-α, IL-1β and M-CSF in the BALF as well as the levels of NF-κB and 8-iso-PGF-2α in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function. These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.

Cell Reports, 2015

Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR)... more Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2007

Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Dat... more Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Our study shows that low LBM is a significan...

Objectives: Periodontal diseases (PD) are chronic infections that may have local and systemic reb... more Objectives: Periodontal diseases (PD) are chronic infections that may have local and systemic rebounds. The aim of this study was to evaluate, comparatively, the substance P (SP), neuronal (nNOS) and inducible (iNOS) nitric oxide syntheses immunoreactivity in gingival samples of patients with severe Periodontal Disease with and without Chronic Craniofacial Pain (CFP). Methods: Inflamed gingival specimens were obtained during routine periodontal surgery for management of 20 patients with PD and Chronic Craniofacial Pain (CFP Group) and of 18 patients with only PD (PD Group). Following surgical removal, the tissue was fixed, embedded in paraffin and 3-4 m sections were cut. Then, tissue samples were submitted to immunohistochemistry and a polyclonal rabbit anti-SP as well as a monoclonal rabbit anti-nNOS and anti-iNOS were used as a primary antibodies. Using an image analysis system, we assessed the SP, nNOS and iNOS content in total gingival tissue as well as in epithelial and connec...

Clinics (São Paulo, Brazil), 2011

To verify the accordance of functional and morphometric parameters during the development of emph... more To verify the accordance of functional and morphometric parameters during the development of emphysema. 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. 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 p...

Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of... more Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of the 2 [high adiposity with low muscle mass (HA-LM)] are relevant phenotypes, but data on their prevalence and impact on health are still limited. This is largely because of a lack of a consensus definition for these conditions. Of particular interest is the HA-LM phenotype, also termed "sarcopenic obesity," which may confer greater health risk. We propose a new approach for operationalizing abnormal body-composition phenotypes in a representative adult population. Whole-body dual-energy X-ray absorptiometry data obtained from the 1999-2004 NHANES were analyzed for 13,236 subjects aged ≥18 y (maximum weight and height of 136 kg and 1.96 m, respectively). Sex- and body mass index (BMI)-specific decile groups of appendicular skeletal muscle index (ASMI; kg/m(2)) and fat mass index (FMI; kg/m(2)) were developed. Cutoffs for HA and LM were incorporated into a diagnostic framework to characterize 4 specific body-composition phenotypes-low adiposity with high muscle mass, high adiposity with high muscle mass, low adiposity with low muscle mass, and HA-LM-and a subclassification of the phenotypes into classes I, II, and III. Abnormal phenotypes were prevalent across the age spectrum and BMI categories. The association between ASMI or FMI and age was modified by sex and BMI. The prevalence of HA-LM in the whole sample was 10.3% in women and 15.2% in men. The prevalence of all subclasses of HA-LM in obese women and men was 14.7% and 22.9%, respectively. HA-LM class III was more prevalent in obese men (2.3%) than in obese women (0.3%). We developed sex- and BMI-specific reference curves to harmonize the classification of body-composition phenotypes. The application of this classification will be particularly useful in the identification of cases of sarcopenic obesity. The association of these phenotypes with metabolic deregulation and increased disease risk awaits verification.

PLoS ONE, 2014

Aims: To determine whether a serine protease inhibitor treatment can prevent or minimize emphysem... more Aims: To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in mice.

Respiratory Physiology & Neurobiology, 2009

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperres... more We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P<0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P<0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics.

Respiratory Physiology & Neurobiology, 2010

We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in air... more We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in airways of guinea pigs (GP) with chronic inflammation. The GP received seven exposures of ovalbumin or saline 0.9%. After 4th inhalation, animals were submitted to repeated forced swim stressor protocol (5×/week/2 weeks). After 7th inhalation, GP were anesthetized. We measured transepithelial potential difference, ciliary beat frequency, mucociliary transport, contact angle, cough transportability and serum cortisol levels. Lungs and adrenals were removed, weighed and analyzed by morphometry. Ovalbumin-exposed animals submitted to repeated stress had a reduction in mucociliary transport, and an increase on serum cortisol, adrenals weight, mucus wettability and adhesivity, positive acid mucus area and IL-4 positive cells in airway compared to non-stressed ovalbumin-exposed animals (p < 0.05). There were no effects on eosinophilic recruitment and IL-13 positive cells. Repeated stress reduces mucociliary clearance due to mucus rheological-property alterations, increasing acid mucus and its wettability and adhesivity. These effects seem to be associated with IL-4 activation.

Respiratory Physiology & Neurobiology, 2009

cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, whic... more cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2 ␣ density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2 ␣ density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

Respiratory Physiology & Neurobiology, 2008

We investigated the effects of substance P (SP) and neurokinin A (NKA) infusion and acute stimula... more We investigated the effects of substance P (SP) and neurokinin A (NKA) infusion and acute stimulation of capsaicin-sensitive sensory nerves fibers (CAP) on lung recruitment of neuronal nitric oxide synthase (nNOS)-positive inflammatory and respiratory sepithelial (RE) cells in guineapigs. We evaluated if the effects of CAP stimulation were maintained until 14 days and had functional pulmonary repercussions. After 24 h of CAP and 30 min after SP and NKA infusions there was an increase in nNOS-positive eosinophils and mononuclear cells compared to controls (P < 0.05). SP group presented an increase in nNOS-positive RE (P < 0.05). After 14 days of CAP stimulation, there was a reduction in resistance (R rs ) and elastance (E rs ) of respiratory system in capsaicin pre-treated animals. We noticed a correlation between nNOS-positive eosinophils (R = −0.644, P < 0.05) and mononuclear cells (R = −0.88, P < 0.001) and R rs . Concluding, CAP and neurokinins increase nNOS expression by inflammatory and RE cells. The increase in nNOS expression induced by low and high doses stimulation of CAP is longstanding and correlated to pulmonary mechanical repercussions.

Neuroimmunomodulation, 2007

Hepatocarcinogenesis in a cirrhotic microenvironment: Experimental model for the study of human h... more Hepatocarcinogenesis in a cirrhotic microenvironment: Experimental model for the study of human hepatocellular carcinoma Abstract Objective

Neuroimmunomodulation, 2012

cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, whic... more cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2 ␣ density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2 ␣ density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

The Lancet Oncology, 2008

Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with d... more Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer.

Journal of Hepatology, 2011

Journal of Applied Physiology, 2008

Nakashima AS, Prado CM, Lanças T, Ruiz VC, Kasahara DI, Leick-Maldonado EA, Dolhnikoff M, Martins... more Nakashima AS, Prado CM, Lanças T, Ruiz VC, Kasahara DI, Leick-Maldonado EA, Dolhnikoff M, Martins MA, Tibério IF. Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs. Recent studies emphasize the presence of alveolar tissue inflammation in asthma. Immunotherapy has been considered a possible therapeutic strategy for asthma, and its effect on lung tissue had not been previously investigated. Measurements of lung tissue resistance and elastance were obtained before and after both ovalbumin and acetylcholine challenges. Using morphometry, we assessed eosinophil and smooth muscle cell density, as well as collagen and elastic fiber content, in lung tissue from guinea pigs with chronic pulmonary allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/ ml; OVA group) or saline (SAL group) during 4 wk. Oral tolerance (OT) was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st inhalation (OT1 group) or after the 4th (OT2 group). The ovalbumin-exposed animals presented an increase in baseline and in postchallenge resistance and elastance related to baseline, eosinophil density, and collagen and elastic fiber content in lung tissue compared with controls. Baseline and postovalbumin and acetylcholine elastance and resistance, eosinophil density, and collagen and elastic fiber content were attenuated in OT1 and OT2 groups compared with the OVA group. Our results show that inducing oral tolerance attenuates lung tissue mechanics, as well as eosinophilic inflammation and extracellular matrix remodeling induced by chronic inflammation. experimental model of chronic allergic pulmonary inflammation; eosinophils; collagen and elastic fibers deposition; lung strip mechanics; tolerization HYPERRESPONSIVENESS, atopy, and chronic eosinophilic and lymphocytic lung inflammation are key features of allergic asthma. Recently, oral tolerance has been recognized as an alternative treatment to autoimmune and allergic diseases . In atopic patients, oral, sublingual, or inhaled administration of antigens leads to a reduction in symptoms and decreased local inflammation, as well as a reduction in dyspnea and airway hyperresponsiveness. A recent meta-analysis found that sublingual immunotherapy is beneficial for asthma treatment, albeit the magnitude of the effect is not very large .

Experimental Lung Research, 2011

The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirc... more The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain.

PloS one, 2014

To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in m... more To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in mice. C57BL/6 mice were subjected to porcine pancreatic elastase (PPE) nasal instillation to induce emphysema and were treated with a serine protease inhibitor (rBmTI-A) before (Protocol 1) and after (Protocol 2) emphysema development. In both protocols, we evaluated lung function to evaluate the airway resistance (Raw), tissue damping (Gtis) and tissue elastance (Htis). The inflammatory profile was analyzed in the bronchoalveolar lavage (BALF) and through the use of morphometry; we measured the mean linear intercept (Lm) (to verify alveolar enlargement), the volume proportion of collagen and elastic fibers, and the numbers of macrophages and metalloprotease 12 (MMP-12) positive cells in the parenchyma. We showed that at both time points, even after the emphysema was established, the rBmTI-A treatment was sufficient to reverse the loss of elastic recoil measured by Htis, the alveolar enla...

Respiratory Research, 2015

Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative... more Pulmonary emphysema is characterized by irreversible airflow obstruction, inflammation, oxidative stress imbalance and lung remodeling, resulting in reduced lung function and a lower quality of life. Flavonoids are plant compounds with potential anti-inflammatory and antioxidant effects that have been used in folk medicine. Our aim was to determine whether treatment with sakuranetin, a flavonoid extracted from the aerial parts of Baccharis retusa, interferes with the development of lung emphysema. Intranasal saline or elastase was administered to mice; the animals were then treated with sakuranetin or vehicle 2 h later and again on days 7, 14 and 28. We evaluated lung function and the inflammatory profile in bronchoalveolar lavage fluid (BALF). The lungs were removed to evaluate alveolar enlargement, extracellular matrix fibers and the expression of MMP-9, MMP-12, TIMP-1, 8-iso-PGF-2α and p65-NF-κB in the fixed tissues as well as to evaluate cytokine levels and p65-NF-κB protein expression. In the elastase-treated animals, sakuranetin treatment reduced the alveolar enlargement, collagen and elastic fiber deposition and the number of MMP-9- and MMP-12-positive cells but increased TIMP-1 expression. In addition, sakuranetin treatment decreased the inflammation and the levels of TNF-α, IL-1β and M-CSF in the BALF as well as the levels of NF-κB and 8-iso-PGF-2α in the lungs of the elastase-treated animals. However, this treatment did not affect the changes in lung function. These data emphasize the importance of oxidative stress and metalloproteinase imbalance in the development of emphysema and suggest that sakuranetin is a potent candidate that should be further investigated as an emphysema treatment. This compound may be useful for counteracting lung remodeling and oxidative stress and thus attenuating the development of emphysema.

Cell Reports, 2015

Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR)... more Obesity is a major risk factor for asthma, which is characterized by airway hyperreactivity (AHR). In obesity-associated asthma, AHR may be regulated by non-TH2 mechanisms. We hypothesized that airway reactivity is regulated by insulin in the CNS, and that the high levels of insulin associated with obesity contribute to AHR. We found that intracerebroventricular (ICV)-injected insulin increases airway reactivity in wild-type, but not in vesicle acetylcholine transporter knockdown (VAChT KD(HOM-/-)), mice. Either neutralization of central insulin or inhibition of extracellular signal-regulated kinases (ERK) normalized airway reactivity in hyperinsulinemic obese mice. These effects were mediated by insulin in cholinergic nerves located at the dorsal motor nucleus of the vagus (DMV) and nucleus ambiguus (NA), which convey parasympathetic outflow to the lungs. We propose that increased insulin-induced activation of ERK in parasympathetic pre-ganglionic nerves contributes to AHR in obese mice, suggesting a drug-treatable link between obesity and asthma.

Clinical cancer research : an official journal of the American Association for Cancer Research, 2007

Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Dat... more Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Data from a prospective study were used to determine if the highest doses of 5-fluorouracil (5-FU) per kilogram LBM would be associated with dose-limiting toxicity in stage II/III colon cancer patients treated with 5-FU and leucovorin. Toxicity after cycle 1 was graded according to National Cancer Institute Common Toxicity Criteria, version 2.0. Muscle tissue was measured by computerized tomography. An extrapolation to the LBM compartment of the whole body was employed. Mean values of 5-FU/LBM of the entire population were different in terms of presence or absence of toxicity (P = 0.036). A cut point of 20 mg 5-FU/kg LBM seemed to be a threshold for developing toxicity (P = 0.005). This observation was pertinent to women (odds ratio, 16.73; P = 0.021). Women in this study had a relatively low proportion of LBM relative to their body surface area. Our study shows that low LBM is a significan...

Objectives: Periodontal diseases (PD) are chronic infections that may have local and systemic reb... more Objectives: Periodontal diseases (PD) are chronic infections that may have local and systemic rebounds. The aim of this study was to evaluate, comparatively, the substance P (SP), neuronal (nNOS) and inducible (iNOS) nitric oxide syntheses immunoreactivity in gingival samples of patients with severe Periodontal Disease with and without Chronic Craniofacial Pain (CFP). Methods: Inflamed gingival specimens were obtained during routine periodontal surgery for management of 20 patients with PD and Chronic Craniofacial Pain (CFP Group) and of 18 patients with only PD (PD Group). Following surgical removal, the tissue was fixed, embedded in paraffin and 3-4 m sections were cut. Then, tissue samples were submitted to immunohistochemistry and a polyclonal rabbit anti-SP as well as a monoclonal rabbit anti-nNOS and anti-iNOS were used as a primary antibodies. Using an image analysis system, we assessed the SP, nNOS and iNOS content in total gingival tissue as well as in epithelial and connec...

Clinics (São Paulo, Brazil), 2011

To verify the accordance of functional and morphometric parameters during the development of emph... more To verify the accordance of functional and morphometric parameters during the development of emphysema. 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. 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 p...

Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of... more Abnormal body compositions such as high adiposity (HA), low muscle mass (LM), or a combination of the 2 [high adiposity with low muscle mass (HA-LM)] are relevant phenotypes, but data on their prevalence and impact on health are still limited. This is largely because of a lack of a consensus definition for these conditions. Of particular interest is the HA-LM phenotype, also termed &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;sarcopenic obesity,&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; which may confer greater health risk. We propose a new approach for operationalizing abnormal body-composition phenotypes in a representative adult population. Whole-body dual-energy X-ray absorptiometry data obtained from the 1999-2004 NHANES were analyzed for 13,236 subjects aged ≥18 y (maximum weight and height of 136 kg and 1.96 m, respectively). Sex- and body mass index (BMI)-specific decile groups of appendicular skeletal muscle index (ASMI; kg/m(2)) and fat mass index (FMI; kg/m(2)) were developed. Cutoffs for HA and LM were incorporated into a diagnostic framework to characterize 4 specific body-composition phenotypes-low adiposity with high muscle mass, high adiposity with high muscle mass, low adiposity with low muscle mass, and HA-LM-and a subclassification of the phenotypes into classes I, II, and III. Abnormal phenotypes were prevalent across the age spectrum and BMI categories. The association between ASMI or FMI and age was modified by sex and BMI. The prevalence of HA-LM in the whole sample was 10.3% in women and 15.2% in men. The prevalence of all subclasses of HA-LM in obese women and men was 14.7% and 22.9%, respectively. HA-LM class III was more prevalent in obese men (2.3%) than in obese women (0.3%). We developed sex- and BMI-specific reference curves to harmonize the classification of body-composition phenotypes. The application of this classification will be particularly useful in the identification of cases of sarcopenic obesity. The association of these phenotypes with metabolic deregulation and increased disease risk awaits verification.

PLoS ONE, 2014

Aims: To determine whether a serine protease inhibitor treatment can prevent or minimize emphysem... more Aims: To determine whether a serine protease inhibitor treatment can prevent or minimize emphysema in mice.

Respiratory Physiology & Neurobiology, 2009

We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperres... more We investigated the effects of oral tolerance (OT) in controlling inflammatory response, hyperresponsiveness and airway remodeling in guinea pigs (GP) with chronic allergic inflammation. Animals received seven inhalations of ovalbumin (1-5mg/mL-OVA group) or normal saline (NS group). OT was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st ovalbumin inhalation (OT1 group) or after the 4th (OT2 group). The induction of OT in sensitized animals decreased the elastance of respiratory system (Ers) response after both antigen and methacholine challenges, peribronchial edema formation, eosinophilic airway infiltration, eosinophilopoiesis, and airways collagen and elastic fiber content compared to OVA group (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). The number of mononuclear cells and resistance of respiratory system (Rrs) responses after antigen and methacholine challenges were decreased only in OT2 group compared to OVA group (P&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;0.05). Concluding, our results show that inducing OT attenuates airway remodeling as well as eosinophilic inflammation and respiratory system mechanics.

Respiratory Physiology & Neurobiology, 2010

We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in air... more We evaluated if repeated stress modulates mucociliary clearance and inflammatory responses in airways of guinea pigs (GP) with chronic inflammation. The GP received seven exposures of ovalbumin or saline 0.9%. After 4th inhalation, animals were submitted to repeated forced swim stressor protocol (5×/week/2 weeks). After 7th inhalation, GP were anesthetized. We measured transepithelial potential difference, ciliary beat frequency, mucociliary transport, contact angle, cough transportability and serum cortisol levels. Lungs and adrenals were removed, weighed and analyzed by morphometry. Ovalbumin-exposed animals submitted to repeated stress had a reduction in mucociliary transport, and an increase on serum cortisol, adrenals weight, mucus wettability and adhesivity, positive acid mucus area and IL-4 positive cells in airway compared to non-stressed ovalbumin-exposed animals (p < 0.05). There were no effects on eosinophilic recruitment and IL-13 positive cells. Repeated stress reduces mucociliary clearance due to mucus rheological-property alterations, increasing acid mucus and its wettability and adhesivity. These effects seem to be associated with IL-4 activation.

Respiratory Physiology & Neurobiology, 2009

cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, whic... more cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2 ␣ density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2 ␣ density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

Respiratory Physiology & Neurobiology, 2008

We investigated the effects of substance P (SP) and neurokinin A (NKA) infusion and acute stimula... more We investigated the effects of substance P (SP) and neurokinin A (NKA) infusion and acute stimulation of capsaicin-sensitive sensory nerves fibers (CAP) on lung recruitment of neuronal nitric oxide synthase (nNOS)-positive inflammatory and respiratory sepithelial (RE) cells in guineapigs. We evaluated if the effects of CAP stimulation were maintained until 14 days and had functional pulmonary repercussions. After 24 h of CAP and 30 min after SP and NKA infusions there was an increase in nNOS-positive eosinophils and mononuclear cells compared to controls (P < 0.05). SP group presented an increase in nNOS-positive RE (P < 0.05). After 14 days of CAP stimulation, there was a reduction in resistance (R rs ) and elastance (E rs ) of respiratory system in capsaicin pre-treated animals. We noticed a correlation between nNOS-positive eosinophils (R = −0.644, P < 0.05) and mononuclear cells (R = −0.88, P < 0.001) and R rs . Concluding, CAP and neurokinins increase nNOS expression by inflammatory and RE cells. The increase in nNOS expression induced by low and high doses stimulation of CAP is longstanding and correlated to pulmonary mechanical repercussions.

Neuroimmunomodulation, 2007

Hepatocarcinogenesis in a cirrhotic microenvironment: Experimental model for the study of human h... more Hepatocarcinogenesis in a cirrhotic microenvironment: Experimental model for the study of human hepatocellular carcinoma Abstract Objective

Neuroimmunomodulation, 2012

cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, whic... more cal evaluation. Stressed animals had higher adrenal weights compared to non-stressed groups, which were reduced by 1400W treatment. Behavioural stress in sensitised animals amplified the resistance and elastance responses after antigen challenge, numbers of eosinophils and iNOS+ cells, actin content and 8-iso-PGF2 ␣ density in the distal lung compared to the OVA group. 1400W treatment in ovalbumin-exposed and stressed animals reduced lung mechanics, iNOS+ cell numbers and 8-iso-PGF2 ␣ density compared to sensitised and stressed animals that received vehicle treatment. We concluded that stress amplifies the distal lung constriction, eosinophilic inflammation, iNOS expression, actin content and oxidative stress previously induced by chronic lung inflammation. iNOS-derived NO contributes to stress-augmented lung tissue functional alterations in this animal model and is at least partially due to activation of the oxidative stress pathway.

The Lancet Oncology, 2008

Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with d... more Background Emerging evidence on body composition suggests that sarcopenic obesity (obesity with depleted muscle mass) might be predictive of morbidity and mortality in non-malignant disease and also of toxicity to chemotherapy. We aimed to assess the prevalence and clinical implications of sarcopenic obesity in patients with cancer.

Journal of Hepatology, 2011

Journal of Applied Physiology, 2008

Nakashima AS, Prado CM, Lanças T, Ruiz VC, Kasahara DI, Leick-Maldonado EA, Dolhnikoff M, Martins... more Nakashima AS, Prado CM, Lanças T, Ruiz VC, Kasahara DI, Leick-Maldonado EA, Dolhnikoff M, Martins MA, Tibério IF. Oral tolerance attenuates changes in in vitro lung tissue mechanics and extracellular matrix remodeling induced by chronic allergic inflammation in guinea pigs. Recent studies emphasize the presence of alveolar tissue inflammation in asthma. Immunotherapy has been considered a possible therapeutic strategy for asthma, and its effect on lung tissue had not been previously investigated. Measurements of lung tissue resistance and elastance were obtained before and after both ovalbumin and acetylcholine challenges. Using morphometry, we assessed eosinophil and smooth muscle cell density, as well as collagen and elastic fiber content, in lung tissue from guinea pigs with chronic pulmonary allergic inflammation. Animals received seven inhalations of ovalbumin (1-5 mg/ ml; OVA group) or saline (SAL group) during 4 wk. Oral tolerance (OT) was induced by offering ad libitum ovalbumin 2% in sterile drinking water starting with the 1st inhalation (OT1 group) or after the 4th (OT2 group). The ovalbumin-exposed animals presented an increase in baseline and in postchallenge resistance and elastance related to baseline, eosinophil density, and collagen and elastic fiber content in lung tissue compared with controls. Baseline and postovalbumin and acetylcholine elastance and resistance, eosinophil density, and collagen and elastic fiber content were attenuated in OT1 and OT2 groups compared with the OVA group. Our results show that inducing oral tolerance attenuates lung tissue mechanics, as well as eosinophilic inflammation and extracellular matrix remodeling induced by chronic inflammation. experimental model of chronic allergic pulmonary inflammation; eosinophils; collagen and elastic fibers deposition; lung strip mechanics; tolerization HYPERRESPONSIVENESS, atopy, and chronic eosinophilic and lymphocytic lung inflammation are key features of allergic asthma. Recently, oral tolerance has been recognized as an alternative treatment to autoimmune and allergic diseases . In atopic patients, oral, sublingual, or inhaled administration of antigens leads to a reduction in symptoms and decreased local inflammation, as well as a reduction in dyspnea and airway hyperresponsiveness. A recent meta-analysis found that sublingual immunotherapy is beneficial for asthma treatment, albeit the magnitude of the effect is not very large .

Experimental Lung Research, 2011

The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirc... more The inducible nitric oxide synthase (iNOS) plays a crucial role in early sepsis-related microcirculatory dysfunction. Compared to a catecholamine therapy we tested effects of a specific iNOS-inhibitor (1400W) on the microcirculatory function in the brain.