Obesity is increasing and is one of our most important health issues. This metabolic disorder is commonly associated with increased systemic inflammation,1,2 which may lead to major adverse events when obese individuals undergo surgical procedures. Anesthetics may influence immune function and the inflammatory process, requiring caution when choosing these agents. Propofol (PRO) and dexmedetomidine (DEX) have a favorable pharmacokinetic profile for anesthesia and sedation and are used for surgical procedures and long-term sedation in intensive care units in the obese population.3–5 In lean animals, PRO decreases airway resistance and lung inflammation in experimental acute lung injury induced by endotoxin,6,7 ischemia–reperfusion,8 or oleic acid.9 Similarly, in lean human subjects, PRO improves lung mechanics,10 reduces inflammation,11 and modulates oxidative stress.12 Likewise, DEX has shown beneficial effects on lung mechanics,13 inflammation,14,15 and oxidative stress16 in lean animals and humans. Conversely, in septic patients with intraabdominal hypertension, PRO, but not DEX , increased tumor necrosis factor (TNF)-α and interleukin (IL)-6 levels.17 However, the impact of these anesthetic/sedative agents on obese populations during short-term procedures is not well established.
In this study, we hypothesized that both PRO and DEX infusion would decrease lung inflammation in obese populations. For this purpose, we compared the short-term effects of DEX versus PRO on lung mechanics and histology, as well as biological markers related to inflammation and oxidative stress modulation in a model of diet-induced obesity.
This study was approved by the Research Ethics Committee of the Federal University of Rio de Janeiro Health Science Centre (CEUA-CCS-019). All animals received humane care in compliance with the Principles of Laboratory Animal Care formulated by the National Society for Medical Research and the United States National Academy of Sciences Guide for the Care and Use of Laboratory Animals.
Animal Preparation and Experimental Protocol
Only clinically healthy male animals were selected for inclusion in the study. Fifty-six male Wistar rats (age, 4 weeks; weight, 100–150 g) were randomly assigned to 2 groups: (1) lean (n = 28), where animals received a conventional diet (commercial rodent chow, Purina®, São Paulo, Brazil) for 12 weeks; and (2) obese group ([Ob] n = 28), in which animals received the experimental diet for the same period. The experimental diet was developed by supplementation of the conventional diet with a tablet, a confectionery product made from sweetened condensed milk (Supplemental Digital Content 1, Supplemental Table 1, http://links.lww.com/AA/B340). To control the environment and reduce potential spread of infectious agents, 3 animals from each group were housed in a microisolator cage (filter tops). All animals were maintained without physical activities, on a 12:12 h light–dark cycle, under controlled temperature conditions, and had unrestricted access to food and water. Food intake was measured every 3 days, and body weight gain was measured once a week. The general characteristics associated with obesity, such as progression of food intake (grams per week), energy intake (kilocalories per week), final body weight (FBW; grams), nasal–anal length (centimeters), and FBW/length (grams per centimeter), were evaluated and did not differ between lean and Ob groups (Supplemental Digital Content 1, Supplemental Table 2, http://links.lww.com/AA/B340). After 12 weeks, animals from the Ob groups received sodium thiopental ([THIO]Thiopentax®, Cristália, Itapira, São Paulo, Brazil) intraperitoneally (50 mg/kg) before undergoing any other procedures. The level of sedation was evaluated by the response to light touch with a fingertip to the rat’s whiskers (0 = awake, fully responsive to surroundings, 1 = not responsive to surroundings, rapid response to whisker stimulation, 2 = slow response, and 3 = unresponsive to whisker stimulation).18 Animals were then placed and kept in the supine position throughout the experiment. The tail vein was cannulated with a 24-gauge catheter, and Ob animals were randomly allocated into 4 subgroups: (1) nonventilated (NV) group (n = 4) for molecular biology analysis only (control); (2) THIO group (n = 8); 3); PROgroup (n = 8); and (4) DEX group (n = 8). In the THIO, PRO, and DEX groups, continuous IV administration of sodium THIO (5 mg/kg/h), PRO (Propovan®, Cristália; 100–200 μg/kg/min for 10 min until an adequate depth of anesthesia was achieved, followed by 75–100 μg/kg/min), or DEX (Precedex®, Hospira, Lake Forest, IL; 1 μg/kg/min bolus over 10 minutes, followed by 0.5 μg/kg/h for maintenance) were administered, respectively. The plane of anesthesia was assessed by evaluation of pupil diameter, position, and response to light; position of the nictitating membrane; and movement in response to tail stimulation. The experiments were started when responses to a noise stimulus (handclap), as well as whisker stimulation and tail clamp response, were absent. A 14-gauge cannula was used for tracheostomy, and a fluid-filled tube was inserted in the esophagus for esophageal pressure measurements. A polyethylene catheter (PE-50) was inserted into the right carotid artery for blood sampling and monitoring of mean arterial blood pressure (MAP). THIO, PRO, and DEX animals’ lungs were mechanically ventilated (Servo-i, Maquet, Solna, Sweden) with the following variables: tidal volume (VT) = 6 mL/kg actual body weight, respiratory rate = 80 breaths/min , fraction of inspired oxygen (FIO2) = 1.0, and positive end-expiratory pressure (PEEP) = 0 cm H2O zero end-expiratory pressure (ZEEP) during the first 5 minutes to evaluate the effects of obesity on lung function without the interference of mechanical ventilation. Blood (300 μL) was drawn into a heparinized syringe to determine arterial oxygen partial pressure (PaO2), arterial partial pressure of carbon dioxide (PaCO2), and arterial pH (pHa; Radiometer ABL80 FLEX, Copenhagen NV, Denmark). Heart rate, MAP, and rectal temperature were continuously recorded (Networked Multiparameter Veterinary Monitor LifeWindow 6000V; Digicare Animal Health, Boynton Beach, FL; baseline ZEEP). Body temperature was maintained at 37.5°C ± 1°C by using a heating blanket. FIO2 was then adjusted to 0.4, PEEP was increased to 3 cm H2O, and functional data were further measured (baseline PEEP). For 1 hour, the anesthesia requirements were adjusted to ensure a similar level of anesthesia in all groups based on maintenance of MAP >70 mm Hg. At the end of the experimental protocol (1 hour), animals were killed by exsanguination, and the lungs were then removed. The exsanguination technique of euthanasia does not interfere with lung histology or with biological markers of inflammation (Supplemental Digital Content 2, Supplemental Figure 1, http://links.lww.com/AA/B334). All experiments were replicated 3 times.
Body Composition Measurements In Vivo—Dual-Energy X-Ray Absorptiometry
After 11 weeks of feeding (1 week before the anesthetic protocol), dual-energy X-ray absorptiometry19 measurements were performed in a Lunar DXA 200368 GE scanner (GE Healthcare, Lunar, WI) using specific software (encore 2008 version 12.20, GE Healthcare) on rats anesthetized by intraperitoneal injection of a 2:1 solution of ketamine hydrochloride (50 mg/mL ketamine, Cristália) and 20 mg/mL xylazine hydrochloride (Rompun Bayer, Animal Health, São Paulo, São Paulo, Brazil). Evaluation was performed in a blind fashion, because the dual-energy X-ray absorptiometry technician was unaware of the experimental protocol. Total fat (% body weight) and trunk fat (% visceral fat) were measured in each animal. All body composition measurements were obtained by one of the authors, blinded to group assignment.
Data Acquisition and Processing
Airflow, volume, and airway and esophageal pressures were measured. Airway pressure (Paw) was measured with a SCIREQ differential pressure transducer (UT-PDP-75, SCIREQ, Montreal, Canada). The changes in esophageal pressure (ΔPes), which reflect changes in chest wall pressure, were measured with a 30-cm long water-filled catheter (PE205) with side holes at the tip connected to a SCIREQ differential pressure transducer (UT-PL-400, SCIREQ). The catheter was passed into the stomach and then slowly returned into the esophagus. Its proper positioning was assessed using the occlusion test.20 Values were continuously recorded using LabView-based software (National Instruments, Austin, TX). All signals were filtered (100 Hz), amplified in a 4-channel conditioner (SC-24; SCIREQ) and sampled at 200 Hz with a 12-bit analog-to-digital converter (National Instruments). Static lung elastance (Est,L) and airway resistance (Raw) were measured by the end-inflation occlusion method and computed offline using a routine written in MATLAB (version R2007a; The Mathworks Inc., Natick, MA).16 All analyses were performed in a blinded manner, i.e., the observer was unaware of the experimental protocol.
Heparin (1000 IU) was injected into the tail vein, the trachea clamped at PEEP 3 cm H2O, and blood aspirated through the arterial line for further analysis, yielding a massive hypovolemia that quickly killed the animals. Lungs were prepared for histological and molecular biology analysis. The retroperitoneal, epididymal, and inguinal adipose tissue compartments were dissected and weighed. Visceral adiposity was estimated by the sum of retroperitoneal and epididymal depot mass and subcutaneous adiposity by the inguinal depot mass.
Lungs were removed en bloc at PEEP = 3 cm H2O in all groups. Lung tissue samples were taken longitudinally from the central zone of the left lung. Sections (4 μm thick) were stained with hematoxylin and eosin. Lung morphometric analysis was performed using an integrating eyepiece with a coherent system consisting of a grid with 100 points and 50 lines of known length coupled to a conventional light microscope (OlympusBX51, Olympus Latin America Inc., São Paulo, SP, Brazil). The volume fractions of the lung occupied by collapsed alveoli (alveoli with rough or plicate walls), hyperinflated structures (alveolar ducts, alveolar sacs, or alveoli wider than 120 μm), and normal pulmonary areas (those not exhibiting overdistended or plicate walls) were determined by the point-counting technique at a magnification of ×200 across 10 random, noncoincident microscopic fields.21 Four intraparenchymatous airways from each animal were viewed at a magnification of ×400. The number of points (NP) falling on the airway lumen and the number of intercepts (NI) of the lines with epithelial basal membrane were counted. Because the NI of the lines with the epithelial basal membrane is proportional to the airway area, the magnitude of bronchoconstriction (contraction index) was computed as contraction index = NI/√NP.22 Lung morphometric analysis was performed in a blinded fashion.
Metabolic and Hormonal Analysis
Serum was separated by centrifugation at 5000 rpm for 10 minutes and stored at −80°C. An enzymatic colorimetric kit (Bioclin, Belo Horizonte, Brazil) was used to measure total triglycerides and total cholesterol in accordance with manufacturer recommendations. Serum insulin and leptin were measured by enzyme-linked immunosorbent assay using commercial kits (EDM, Millipore, Corporation, MA). The assay sensitivity was 0.1 ng/dL for rat insulin and 0.08 ng/dL for leptin, and the intraassay coefficients of variation were <3% and <10%, respectively. All metabolic and hormonal analyses were performed by one of the authors, blinded to group assignment.
Biological Markers of Proinflammatory and Oxidative Stress Activity in Lung and Adipose Tissue
Quantitative real-time reverse transcription polymerase chain reaction (PCR) was performed to measure biological markers associated with inflammation (TNF-α and IL-6) and oxidative stress (nuclear factor erythroid 2-derived factor-2 [Nrf2], catalase [CAT], and glutathione peroxidase [GPx]) in the lung tissue and IL-6 in the adipose tissue. Acidic ribosomal phosphoprotein P0 (36B4) was used as a housekeeping gene.23 Central slices of right lung and visceral adipose tissue were cut, collected in cryotubes, quick frozen by immersion in liquid nitrogen, and stored at −80°C. Total RNA was extracted from frozen tissues using the Quantitec Reverse Transcription total RNA Isolation System (Qiagen Corporation, Valencia, CA), following manufacturer recommendations. RNA concentration was measured by spectrophotometry in a Nanodrop® ND-1000 system (Thermo Fisher Scientific, Wilmington, DE). First-strand complementary DNA was synthesized from total RNA using the GoTaq® 2-STEP RT-Quantitative PCR System (Promega Corporation, Fitchburg, WI). The primers (Invitrogen, Carlsbad, CA) used for gene amplification are listed in Supplemental Digital Content 1, Supplemental Table 3 (http://links.lww.com/AA/B340). Relative mRNA levels were measured with a SYBR green detection system in an ABI 7500 Real-Time PCR system (Applied Biosystems, Foster City, CA). Samples were measured in triplicate. Relative gene expression was calculated as a ratio of the average gene expression levels compared with the reference gene (36B4) using the 2−ΔΔ,Ct method, where ΔCt = Ct (reference gene) − Ct (target gene) and expressed as fold changes relative to NV animals (Ob NV) before the start of anesthesia protocols. Lung biological analyses were performed in a blinded fashion by one of the authors.
The sample size calculation for testing the primary hypothesis was based on the decrease in lung inflammation as measured by mRNA expression of IL-6 after DEX infusion in endotoxin-induced shock in rats. The mean (SD) of IL-6 mRNA expression was 1 (0.64) in lean animals and 300 (240) in animals subjected to endotoxin-induced shock.14
Accordingly, adjusting the α error probability to 5% and the statistical power to 95%, we obtained a sample size of 8 animals per group. This sample size would provide the appropriate power (1−β = 0.95) to identify significant (α = 0.05) differences in IL-6 gene expression, considering an effect size d = 1.76, a 2-sided test, and a sample size ratio = 1 (G*Power 184.108.40.206, University of Düsseldorf, Germany).
Random allocation was performed by simple randomization using computer-generated sequence. To characterize the model of obesity, data from lean animals were compared with those obtained for Ob rats using the Student t test. Concerning the effects of sodium THIO, PRO, or DEX in Ob rats, different variables were compared using 1-way analysis of variance followed by the Bonferroni post hoc test. For molecular biology analyses, Student t tests with P values adjusted for multiple comparisons (n = 3, α* = 0.0167, α* Bonferroni-adjusted test) were performed among the 3 drugs versus NV animals. We used Kolmogorov-Smirnov test with Lilliefors correction and Levene median test to assess normality and the equality of variance, respectively, to all of the analysis of variance residuals, with all P values ≥0.17. Parametric data were expressed as mean (SD) and nonparametric data as median (interquartile range). All tests were performed using GraphPad Prism version 5.00 (GraphPad Software, La Jolla, CA). Significance was established at P < 0.05.
All animals survived the 12-week dietary intervention period and the anesthetic experimental protocol.
Comparison Between Lean and Obese Animals
Body and trunk fat percentages were higher in Ob animal groups compared with lean animals (Supplemental Digital Content 1, Supplemental Table 4, http://links.lww.com/AA/B340). Furthermore, Ob animal groups showed higher triglyceride, total cholesterol, insulin, and leptin levels (Supplemental Digital Content 1, Supplemental Table 5, http://links.lww.com/AA/B340). Although no differences were observed in general characteristics, such as body weight (Supplemental Digital Content 1, Supplemental Table 2, http://links.lww.com/AA/B340), adipose tissue compartments normalized by FBW were significantly greater in Ob compared with lean animals (P = 0.0001) (Supplemental Digital Content 1, Supplemental Table 6, http://links.lww.com/AA/B340). Est,L did not differ significantly between lean and Ob animals (P = 0.17). Raw was higher in Ob animal groups compared with lean animals (P = 0.0027). Alveolar collapse was greater in Ob animal groups than in lean rats (Supplemental Digital Content 1, Supplemental Table 7, http://links.lww.com/AA/B340). In addition, mRNA expression of IL-6 in lung and adipose tissues was higher in Ob animal groups than in lean animals (P = 0.01; Fig. 1).
Effects of Sodium Thiopental, Propofol, and Dexmedetomidine in Obese Rats
No differences were observed in MAP (Supplemental Digital Content 3, Supplemental Figure 2, http://links.lww.com/AA/B341). Likewise, blood gas analyses were comparable among Ob groups at baseline ZEEP (Supplemental Digital Content 1, Supplemental Table 8, http://links.lww.com/AA/B340). Furthermore, Est,L and Raw were also similar in all groups at baseline PEEP (Supplemental Digital Content 1, Supplemental Table 9, http://links.lww.com/AA/B340).
After 1 hour of drug infusion and mechanical ventilation, Est,L did not differ across groups administered different agents (THIO: 1.9 ± 0.7; PRO: 2.3 ± 0.5; DEX: 2.1 ± 0.3). Conversely, Ob PRO animals demonstrated a higher Raw compared with Ob THIO (P = 0.001) and Ob DEX (P = 0.016) animals (Lilliefors correction, P = 0.854; Levene median test, P = 0.732; Fig. 2). After drug infusion, alveolar collapse was greater in Ob PRO animals compared with Ob DEX animals, and the bronchoconstriction index was higher in Ob PRO animals compared with Ob THIO and Ob DEX animals (P = 0.04; all P ≥ 0.17 for Lilliefors correction and Levene median test; Table 1). Figure 3 depicts light micrographs of representative animals in each group, clearly showing a reduction in airway diameter in the Ob PRO group.
Biological Markers Associated with Inflammation and Oxidative Stress After Propofol or Dexmedetomidine Administration in Obese Rats
Figures 4 and 5 show the expression of markers associated with inflammation and oxidative stress, respectively, in the Ob groups. PRO led to higher mRNA expression of IL-6 and TNF-α and lower expression of GPx, an antioxidative enzyme, than in the NV group (Figs. 4 and 5). Regarding modulation of oxidative stress, the THIO group exhibited lower mRNA expression of Nrf2 and CAT compared with NV group (Fig. 5). Unlike PRO and THIO, DEX infusion did not modify the biological variables related to inflammation and oxidative stress modulation (Figs. 4 and 5).
In our model of diet-induced obesity, a 1-hour PRO infusion yielded increased airway resistance, atelectasis, and lung inflammation with depletion of antioxidative enzymes. As a short-term infusion, DEX had no impact on lung mechanical and histology, as well as biological variables, unlike sodium THIO and PRO.
Relevance of the Diet-Induced Obesity Model
We developed a model of obesity that features increased total body fat content, central adiposity, and a metabolic profile such as increased leptinemia, insulinemia, and dyslipidemia,24 yet did not increase body weight compared with lean animals. Furthermore, our model featured increased expression of IL-6 in lung and adipose tissues, suggesting systemic inflammation associated with obesity.25
At the start of the experimental protocol, sodium THIO was administered in all groups to prevent discomfort associated with surgical manipulation. In addition, sodium THIO does not affect baseline airway tone,26 lung mechanics, or histology.16,26 A protective ventilatory strategy was used to discard possible biological effects associated with mechanical ventilation, which may yield confounding results. Infusion rates of sodium THIO, PRO, and DEX were based on experimental studies that reported negligible effects of these agents on hemodynamic variables in rats6,14,16 when given for 1 hour. Although the initial bolus dose of DEX is considered high compared with that recommended for humans, animals reached an adequate anesthesia level not observed with lower doses, without autonomic derangements or cardiovascular compromise. Because obesity may affect drug metabolism, depth of anesthesia and hemodynamic variables were strictly controlled.
Choice of Anesthetic Agent
There has been controversy concerning the optimal sedative/anesthetic agent for use in short-term procedures in the obese population.3,5,27 PRO and DEX have been used because they have favorable pharmacokinetic properties, allow easy titration of sedation/anesthesia and maintenance of steady-state drug levels, and yield rapid recovery.27
Effects of Propofol and Dexmedetomidine on Lung Mechanics and Histology
PRO increased Raw compared with sodium THIO and DEX in Ob animals, in contrast to what has been observed in in vitro studies,28 animals without obesity,29 and lean humans.30 PRO can trigger bronchospasm during anesthetic induction, which is associated with the effects of metabisulfite preservative on neurally mediated and direct airway smooth muscle-induced bronchoconstriction.31 In Ob animals, the release of proinflammatory mediators produced in adipose tissue contributes to a state of systemic and lung inflammation,25 which, in association with PRO or its preservative, may exacerbate airway obstruction.32 The exact mechanism of bronchoconstriction induced by PRO (2,6-diisopropylphenol) or its excipients is not completely understood and might include activation of tracheobronchial irritant receptors and stimulation of a cholinergic reflex33 or nonallergic bronchospasm.34 In our study, the PRO used (produced by Cristália) did not contain EDTA or sodium metabisulfite, but the following additives were listed: soybean oil, egg lecithin, glycerol, oleic acid, sodium hydroxide, and water. These cannot be excluded as factors leading to worsening of airway resistance.
Inflammation and Oxidative Stress After Propofol and Dexmedetomidine Administration in Obesity
The proinflammatory cytokines, TNF-α2 and IL-6,25,35 exert important roles in the immune mechanisms linked to obesity. TNF-α is important concerning the expansion of adipose tissue mass through macrophage recruitment and is implicated in induction of airway hyperresponsiveness.36IL-6, important in the regulation of inflammatory and immune responses,35 is considered a marker of visceral adiposity.37Nrf2 regulates antioxidant defenses that protect against inflammation by inhibiting oxidative tissue injury.38GPx acts as a reducing system for H2O2 and detoxifies several toxic peroxides, preventing lipid peroxidation.39CAT catalyzes H2O2 dismutation and protects cells against the harmful effects of H2O2.40 After confirming lung and systemic inflammation in our obesity model by measuring IL-6 expression, we normalized molecular biology analyses by a NV (Ob NV) group. IL-6 and TNF-α expressions were higher in Ob PRO compared with NV animals, which may have been because of the interaction between increased leptin levels and PRO exposure. In our study, the higher levels of leptin may have contributed to the release of proinflammatory mediators through epithelial cells, airway smooth muscle cells, and macrophages,41 which express the leptin receptor. PRO and its intralipid diluent considerably depress neutrophil chemotaxis42 and function at 50%.43 We hypothesize that by decreasing neutrophil function, these cells (epithelial cells, airway smooth muscle cells, and macrophages) may activate the nuclear factor-κB pathway to keep the neutrophil activity requirement in the setting of obesity. DEX did not affect the expression of IL-6 and TNF-α, and subjects’ responses to it resembled those to sodium THIO. These findings stand in contrast to what has been reported in experimental sepsis14,15 and in clinical studies44 in which DEX inhibited inflammation because of its sympatholytic effects, resulting in downregulation of proinflammatory cytokines.45
GPx activity is decreased in obese compared with non-obese subjects.46 PRO reduced GPx expression, which was not affected by DEX and sodium THIO. This is in contrast to previous reports, because the PRO structure contains a phenolic hydroxyl group, important for free radical scavenging activities and considered a peroxynitrite-mediated oxidative stress scavenger in healthy subjects, with established antioxidant properties.47 The increased oxidative stress because of the association between PRO and obesity may be explained by higher leptin levels in Ob animals, because leptin is directly related to increased oxidative stress in different tissues and cells in response to inflammatory stress.48
This study has some limitations: (1) The effects of PRO on different models of lung inflammation differ according to dose.6,49 In our study, results were based on an adequate level of anesthesia and hemodynamics, rather than the dose in Ob animals. No study has evaluated the dose adjustment of PRO or DEX in obese rats. Analysis of a progressive drug dose response or plasma concentration at the effect site should be better evaluated in future research. (2) All Ob animals’ lungs were ventilated with VT = 6 mL/kg actual body weight, PEEP = 3 cm H2O, and no recruitment maneuvers. In animal species, although lean body mass or species-specific adjusted body weight may be appropriate variables, additional studies to determine excess lean body mass associated with adiposity in small animals would help define body weight–adjusted dosing strategies.50 In this study, VT was set according to actual body weight, because body weight did not differ between lean and Ob animals and there is no validated body mass index for rats. The PEEP level was set based on the pilot studies in Ob animals; however, we cannot exclude that different results could have been obtained at higher or lower PEEP levels and/or with associated recruitment maneuvers. (3) Our results cannot be directly extrapolated to the clinical setting or other obesity models. (4) Observation time was relatively short (1 hour of anesthetic infusion); however, a longer time course may result in confounding data because of fluid requirement to maintain MAP at adequate levels, which affects inflammatory markers. (5) We focused on specific inflammatory and oxidative stress mediators involved in obesity-associated systemic inflammation. Another study is required to detail the mechanisms associated with individual gene activation and the possible mechanisms of action of PRO in the setting of obesity.
Before a clinical study is undertaken to evaluate the role of PRO in obese patients, further experimental studies are required to clarify the interactions between PRO and hyperleptinemia or adipocytokines in obesity.
In a model of diet-induced obesity, a 1-hour PRO infusion yielded increased airway resistance, atelectasis, and lung inflammation, with depletion of antioxidative enzymes. Unlike sodium THIO and PRO, short-term infusion of DEX had no impact on lung morphofunctional and biological variables.
Name: Luciana Boavista Barros Heil, MD.
Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Luciana Boavista Barros Heil approved the final manuscript, attests to the integrity of the original data and the analysis reported in this manuscript, and is the archival author.
Name: Cíntia L. Santos, PhD.
Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Cíntia L. Santos approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Raquel S. Santos, PhD.
Contribution: This author helped design the study, conduct the study, collect the data, and analyze the data.
Attestation: Raquel S. Santos approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Cynthia S. Samary, PhD.
Contribution: This author helped design the study, conduct the study, and collect the data.
Attestation: Cynthia S. Samary approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Vinicius C. M. Cavalcanti, MD, MSc.
Contribution: This author helped conduct the study and collect the data.
Attestation: Vinicius C. M. Cavalcanti approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Mariana M. P. N. Araújo, MD.
Contribution: This author helped conduct the study and collect the data.
Attestation: Mariana M. P. N. Araújo approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Hananda Poggio, PhD.
Contribution: This author helped conduct the study, collect the data, and analyze the data.
Attestation: Hananda Poggio approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Lígia de A. Maia, PhD.
Contribution: This author helped collect the data, analyze the data, and prepare the manuscript.
Attestation: Lígia de A. Maia approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Isis Hara Trevenzoli, PhD.
Contribution: This author helped conduct the study, analyze the data, and prepare the manuscript.
Attestation: Isis Hara Trevenzoli approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Paolo Pelosi, MD, FERS.
Contribution: This author helped design the study, analyze the data, and prepare the manuscript.
Attestation: Paolo Pelosi approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Fatima C. Fernandes, MD, PhD.
Contribution: This author helped design the study and analyze the data.
Attestation: Fatima C. Fernandes approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Nivaldo R. Villela, MD, PhD.
Contribution: This author helped design the study and analyze the data.
Attestation: Nivaldo R. Villela approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Pedro L. Silva, PhD.
Contribution: This author helped design the study, conduct the study, collect the data, analyze the data, and prepare the manuscript.
Attestation: Pedro L. Silva approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
Name: Patricia R. M. Rocco, MD, PhD.
Contribution: This author helped design the study, conduct the study, analyze the data, and prepare the manuscript.
Attestation: Patricia R. M. Rocco approved the final manuscript and attests to the integrity of the original data and the analysis reported in this manuscript.
This manuscript was handled by: Markus W. Hollmann, MD, PhD, DEAA.
The authors thank Mr. Andre Benedito da Silva for animal care; Mrs. Ana Lucia Neves da Silva for her help with microscopy; Professor Ronir Raggio Luiz, PhD (Institute of Public Health Studies, Federal University of Rio de Janeiro) for his help with statistics; and MAQUET (São Paulo, Brazil) for technical support.
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