Cynthia S. Samary

Hypervolemia induces and potentiates lung damage after recruitment maneuver in a model of sepsis-induced acute lung injury

IntroductionRecruitment maneuvers (RMs) seem to be more effective in extrapulmonary acute lung injury (ALI), caused mainly by sepsis, than in pulmonary ALI. Nevertheless, the maintenance of adequate volemic status is particularly challenging in sepsis. Since the interaction between volemic status and RMs is not well established, we investigated the effects of RMs on lung and distal organs in the presence of hypovolemia, normovolemia, and hypervolemia in a model of extrapulmonary lung injury induced by sepsis.MethodsALI was induced by cecal ligation and puncture surgery in 66 Wistar rats. After 48 h, animals were anesthetized, mechanically ventilated and randomly assigned to 3 volemic status (n = 22/group): 1) hypovolemia induced by blood drainage at mean arterial pressure (MAP)≈70 mmHg; 2) normovolemia (MAP≈100 mmHg), and 3) hypervolemia with colloid administration to achieve a MAP≈130 mmHg. In each group, animals were further randomized to be recruited (CPAP = 40 cm H2O for 40 s) or not (NR) (n = 11/group), followed by 1 h of protective mechanical ventilation. Echocardiography, arterial blood gases, static lung elastance (Est,L), histology (light and electron microscopy), lung wet-to-dry (W/D) ratio, interleukin (IL)-6, IL-1β, caspase-3, type III procollagen (PCIII), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1) mRNA expressions in lung tissue, as well as lung and distal organ epithelial cell apoptosis were analyzed.ResultsWe observed that: 1) hypervolemia increased lung W/D ratio with impairment of oxygenation and Est,L, and was associated with alveolar and endothelial cell damage and increased IL-6, VCAM-1, and ICAM-1 mRNA expressions; and 2) RM reduced alveolar collapse independent of volemic status. In hypervolemic animals, RM improved oxygenation above the levels observed with the use of positive-end expiratory pressure (PEEP), but increased lung injury and led to higher inflammatory and fibrogenetic responses.ConclusionsVolemic status should be taken into account during RMs, since in this sepsis-induced ALI model hypervolemia promoted and potentiated lung injury compared to hypo- and normovolemia.

Recruitment maneuvers modulate epithelial and endothelial cell response according to acute lung injury etiology.

Objective:To investigate the effects of the rate of increase in airway pressure and duration of lung recruitment maneuvers in experimental pulmonary and extrapulmonary acute lung injury. Design:Prospective, randomized, controlled experimental study. Settings:University research laboratory. Subjects:Fifty adult male Wistar rats. Interventions:Acute lung injury was induced by Escherichia coli lipopolysaccharide either intratracheally (pulmonary acute lung injury) or intraperitoneally (extrapulmonary acute lung injury). After 24 hours, animals were assigned to one of three different recruitment maneuvers, targeted to maximal airway pressure of 30 cm H2O: 1) continuous positive airway pressure for 30 seconds (CPAP-30); 2) stepwise airway pressure increase (5 cm H2O/step, 8.5 s at each step) over 51 seconds (STEP-51) to achieve a pressure-time product similar to that of CPAP-30; and 3) stepwise airway pressure increase (5 cm H2O/step, 5 s at each step) over 30 seconds with maximum pressure sustained for a further 30 seconds (STEP-30/30). Measurements and Main Results:All recruitment maneuvers reduced static lung elastance independent of acute lung injury etiology. In pulmonary acute lung injury, CPAP-30 yielded lower surfactant protein-B and higher type III procollagen expressions compared with STEP-30/30. In extrapulmonary acute lung injury, CPAP-30 and STEP-30/30 increased vascular cell adhesion molecule-1 expression, but the type of recruitment maneuver did not influence messenger ribonucleic acid expression of receptor for advanced glycation end products, surfactant protein-B, type III procollagen, and pro-caspase 3. Conclusions:CPAP-30 worsened markers of potential epithelial cell damage in pulmonary acute lung injury, whereas both CPAP-30 and STEP-30/30 yielded endothelial injury in extrapulmonary acute lung injury. In both acute lung injury groups, recruitment maneuvers improved respiratory mechanics, but stepwise recruitment maneuver without sustained airway pressure appeared to associate with less biological impact on lungs.

Impact of pressure profile and duration of recruitment maneuvers on morphofunctional and biochemical variables in experimental lung injury.

Objective:To investigate the effects of the rate of airway pressure increase and duration of recruitment maneuvers on lung function and activation of inflammation, fibrogenesis, and apoptosis in experimental acute lung injury. Design:Prospective, randomized, controlled experimental study. Setting:University research laboratory. Subjects:Thirty-five Wistar rats submitted to acute lung injury induced by cecal ligation and puncture. Interventions:After 48 hrs, animals were randomly distributed into five groups (seven animals each): 1) nonrecruited (NR); 2) recruitment maneuvers (RMs) with continuous positive airway pressure (CPAP) for 15 secs (CPAP15); 3) RMs with CPAP for 30 secs (CPAP30); 4) RMs with stepwise increase in airway pressure (STEP) to targeted maximum within 15 secs (STEP15); and 5) RMs with STEP within 30 secs (STEP30). To perform STEP RMs, the ventilator was switched to a CPAP mode and positive end-expiratory pressure level was increased stepwise. At each step, airway pressure was held constant. RMs were targeted to 30 cm H2O. Animals were then ventilated for 1 hr with tidal volume of 6 mL/kg and positive end-expiratory pressure of 5 cm H2O. Measurements and Main Results:Blood gases, lung mechanics, histology (light and electronic microscopy), interleukin-6, caspase 3, and type 3 procollagen mRNA expressions in lung tissue. All RMs improved oxygenation and lung static elastance and reduced alveolar collapse compared to NR. STEP30 resulted in optimal performance, with: 1) improved lung static elastance vs. NR, CPAP15, and STEP15; 2) reduced alveolar-capillary membrane detachment and type 2 epithelial and endothelial cell injury scores vs. CPAP15 (p < .05); and 3) reduced gene expression of interleukin-6, type 3 procollagen, and caspase 3 in lung tissue vs. other RMs. Conclusions:Longer-duration RMs with slower airway pressure increase efficiently improved lung function, while minimizing the biological impact on lungs.

Biological impact of transpulmonary driving pressure in experimental acute respiratory distress syndrome

Background:Ventilator-induced lung injury has been attributed to the interaction of several factors: tidal volume (VT), positive end-expiratory pressure (PEEP), transpulmonary driving pressure (difference between transpulmonary pressure at end-inspiration and end-expiration, &Dgr;P,L), and respiratory system plateau pressure (Pplat,rs). Methods:Forty-eight Wistar rats received Escherichia coli lipopolysaccharide intratracheally. After 24 h, animals were randomized into combinations of VT and PEEP, yielding three different &Dgr;P,L levels: &Dgr;P,LLOW (VT = 6 ml/kg, PEEP = 3 cm H2O); &Dgr;P,LMEAN (VT = 13 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 9.5 cm H2O); and &Dgr;P,LHIGH (VT = 22 ml/kg, PEEP = 3 cm H2O or VT = 6 ml/kg, PEEP = 11 cm H2O). In other groups, at low VT, PEEP was adjusted to obtain a Pplat,rs similar to that achieved with &Dgr;P,LMEAN and &Dgr;P,LHIGH at high VT. Results:At &Dgr;P,LLOW, expressions of interleukin (IL)-6, receptor for advanced glycation end products (RAGE), and amphiregulin were reduced, despite morphometric evidence of alveolar collapse. At &Dgr;P,LHIGH (VT = 6 ml/kg and PEEP = 11 cm H2O), lungs were fully open and IL-6 and RAGE were reduced compared with &Dgr;P,LMEAN (27.4 ± 12.9 vs. 41.6 ± 14.1 and 0.6 ± 0.2 vs. 1.4 ± 0.3, respectively), despite increased hyperinflation and amphiregulin expression. At &Dgr;P,LMEAN (VT = 6 ml/kg and PEEP = 9.5 cm H2O), when PEEP was not high enough to keep lungs open, IL-6, RAGE, and amphiregulin expression increased compared with &Dgr;P,LLOW (41.6 ± 14.1 vs. 9.0 ± 9.8, 1.4 ± 0.3 vs. 0.6 ± 0.2, and 6.7 ± 0.8 vs. 2.2 ± 1.0, respectively). At Pplat,rs similar to that achieved with &Dgr;P,LMEAN and &Dgr;P,LHIGH, higher VT and lower PEEP reduced IL-6 and RAGE expression. Conclusion:In the acute respiratory distress syndrome model used in this experiment, two strategies minimized ventilator-induced lung injury: (1) low VT and PEEP, yielding low &Dgr;P,L and Pplat,rs; and (2) low VT associated with a PEEP level sufficient to keep the lungs open.

Regular and moderate exercise before experimental sepsis reduces the risk of lung and distal organ injury

Physical activity modulates inflammation and immune response in both normal and pathologic conditions. We investigated whether regular and moderate exercise before the induction of experimental sepsis reduces the risk of lung and distal organ injury and survival. One hundred twenty-four BALB/c mice were randomly assigned to two groups: sedentary (S) and trained (T). Animals in T group ran on a motorized treadmill, at moderate intensity, 5% grade, 30 min/day, 3 times a week for 8 wk. Cardiac adaptation to exercise was evaluated using echocardiography. Systolic volume and left ventricular mass were increased in T compared with S group. Both T and S groups were further randomized either to sepsis induced by cecal ligation and puncture surgery (CLP) or sham operation (control). After 24 h, lung mechanics and histology, the degree of cell apoptosis in lung, heart, kidney, liver, and small intestine villi, and interleukin (IL)-6, KC (IL-8 murine functional homolog), IL-1β, IL-10, and number of cells in bronchoalveolar lavage (BALF) and peritoneal lavage (PLF) fluids as well as plasma were measured. In CLP, T compared with S groups showed: 1) improvement in survival; 2) reduced lung static elastance, alveolar collapse, collagen and elastic fiber content, number of neutrophils in BALF, PLF, and plasma, as well as lung and distal organ cell apoptosis; and 3) increased IL-10 in BALF and plasma, with reduced IL-6, KC, and IL-1β in PLF. In conclusion, regular and moderate exercise before the induction of sepsis reduced the risk of lung and distal organ damage, thus increasing survival.

DNA nanoparticle-mediated thymulin gene therapy prevents airway remodeling in experimental allergic asthma

Thymulin has been shown to present anti-inflammatory and anti-fibrotic properties in experimental lung diseases. We hypothesized that a biologically active thymulin analog gene, methionine serum thymus factor, delivered by highly compacted DNA nanoparticles may prevent lung inflammation and remodeling in a mouse model of allergic asthma. The DNA nanoparticles are composed of a single molecule of plasmid DNA compacted with block copolymers of poly-L-lysine and polyethylene glycol (CK30PEG), which have been found safe in a human phase I/II clinical trial. Thymulin plasmids were detected in the lungs of ovalbumin-challenged asthmatic mice up to 27days after administration of DNA nanoparticles carrying thymulin plasmids. A single dose of DNA nanoparticles carrying thymulin plasmids prevented lung inflammation, collagen deposition and smooth muscle hypertrophy in the lungs of a murine model of ovalbumin-challenged allergic asthma, leading to improved lung mechanics. In the present model of chronic allergic asthma, highly compacted DNA nanoparticles using thymulin analog gene modulated the inflammatory and remodeling processes improving lung mechanics.

Modulation of stress versus time product during mechanical ventilation influences inflammation as well as alveolar epithelial and endothelial response in rats.

Background:Mechanical ventilation can lead to lung biotrauma when mechanical stress exceeds safety thresholds. The authors investigated whether the duration of mechanical stress, that is, the impact of a stress versus time product (STP), influences biotrauma. The authors hypothesized that higher STP levels are associated with increased inflammation and with alveolar epithelial and endothelial cell injury. Methods:In 46 rats, Escherichia coli lipopolysaccharide (acute lung inflammation) or saline (control) was administered intratracheally. Both groups were protectively ventilated with inspiratory-to-expiratory ratios 1:2, 1:1, or 2:1 (n = 12 each), corresponding to low, middle, and high STP levels (STPlow, STPmid, and STPhigh, respectively). The remaining 10 animals were not mechanically ventilated. Results:In animals with mild acute lung inflammation, but not in controls: (1) messenger RNA expression of interleukin-6 was higher in STPhigh (28.1 ± 13.6; mean ± SD) and STPlow (28.9 ± 16.0) versus STPmid (7.4 ± 7.5) (P < 0.05); (2) expression of the receptor for advanced glycation end-products was increased in STPhigh (3.6 ± 1.6) versus STPlow (2.3 ± 1.1) (P < 0.05); (3) alveolar edema was decreased in STPmid (0 [0 to 0]; median, Q1 to Q3) compared with STPhigh (0.8 [0.6 to 1]) (P < 0.05); and (4) expressions of vascular cell adhesion molecule-1 and intercellular adhesion molecule-1 were higher in STPlow (3.0 ± 1.8) versus STPhigh (1.2 ± 0.5) and STPmid (1.4 ± 0.7) (P < 0.05), respectively. Conclusions:In the mild acute lung inflammation model used herein, mechanical ventilation with inspiratory-to-expiratory of 1:1 (STPmid) minimized lung damage, whereas STPhigh increased the gene expression of biological markers associated with inflammation and alveolar epithelial cell injury and STPlow increased markers of endothelial cell damage.

Lung Functional and Biologic Responses to Variable Ventilation in Experimental Pulmonary and Extrapulmonary Acute Respiratory Distress Syndrome

Objectives: The biologic effects of variable ventilation may depend on the etiology of acute respiratory distress syndrome. We compared variable and conventional ventilation in experimental pulmonary and extrapulmonary acute respiratory distress syndrome. Design: Prospective, randomized, controlled experimental study. Settings: University research laboratory. Subjects: Twenty-four Wistar rats. Interventions: Acute respiratory distress syndrome was induced by Escherichia coli lipopolysaccharide administered intratracheally (pulmonary acute respiratory distress syndrome, n = 12) or intraperitoneally (extrapulmonary acute respiratory distress syndrome, n = 12). After 24 hours, animals were randomly assigned to receive conventional (volume-controlled ventilation, n = 6) or variable ventilation (n = 6). Nonventilated animals (n = 4 per etiology) were used for comparison of diffuse alveolar damage, E-cadherin, and molecular biology variables. Variable ventilation was applied on a breath-to-breath basis as a sequence of randomly generated tidal volume values (n = 600; mean tidal volume = 6 mL/kg), with a 30% coefficient of variation (normal distribution). After randomization, animals were ventilated for 1 hour and lungs were removed for histology and molecular biology analysis. Measurements and Main Results: Variable ventilation improved oxygenation and reduced lung elastance compared with volume-controlled ventilation in both acute respiratory distress syndrome etiologies. In pulmonary acute respiratory distress syndrome, but not in extrapulmonary acute respiratory distress syndrome, variable ventilation 1) decreased total diffuse alveolar damage (median [interquartile range]: volume-controlled ventilation, 12 [11–17] vs variable ventilation, 9 [8–10]; p < 0.01), interleukin-6 expression (volume-controlled ventilation, 21.5 [18.3–23.3] vs variable ventilation, 5.6 [4.6–12.1]; p < 0.001), and angiopoietin-2/angiopoietin-1 ratio (volume-controlled ventilation, 2.0 [1.3–2.1] vs variable ventilation, 0.7 [0.6–1.4]; p < 0.05) and increased relative angiopoietin-1 expression (volume-controlled ventilation, 0.3 [0.2–0.5] vs variable ventilation, 0.8 [0.5–1.3]; p < 0.01). In extrapulmonary acute respiratory distress syndrome, only volume-controlled ventilation increased vascular cell adhesion molecule-1 messenger RNA expression (volume-controlled ventilation, 7.7 [5.7–18.6] vs nonventilated, 0.9 [0.7–1.3]; p < 0.05). E-cadherin expression in lung tissue was reduced in volume-controlled ventilation compared with nonventilated regardless of acute respiratory distress syndrome etiology. In pulmonary acute respiratory distress syndrome, E-cadherin expression was similar in volume-controlled ventilation and variable ventilation; in extrapulmonary acute respiratory distress syndrome, however, it was higher in variable ventilation than in volume-controlled ventilation. Conclusions: Variable ventilation improved lung function in both pulmonary acute respiratory distress syndrome and extrapulmonary acute respiratory distress syndrome. Variable ventilation led to more pronounced beneficial effects in biologic marker expressions in pulmonary acute respiratory distress syndrome compared with extrapulmonary acute respiratory distress syndrome but preserved E-cadherin in lung tissue only in extrapulmonary acute respiratory distress syndrome, thus suggesting lower damage to epithelial cells.

The Effects of Short-Term Propofol and Dexmedetomidine on Lung Mechanics, Histology, and Biological Markers in Experimental Obesity.

BACKGROUND:Administering anesthetics to the obese population requires caution because of a variety of reasons including possible interactions with the inflammatory process observed in obese patients. Propofol and dexmedetomidine have protective effects on pulmonary function and are widely used in short- and long-term sedation, particularly in intensive care unit settings in lean and obese subjects. However, the functional and biological effects of these drugs in obesity require further elucidation. In a model of diet-induced obesity, we compared the short-term effects of dexmedetomidine versus propofol on lung mechanics and histology, as well as biological markers of inflammation and oxidative stress modulation in obesity. METHODS:Wistar rats (n = 56) were randomly fed a standard diet (lean) or experimental diet (obese) for 12 weeks. After this period, obese animals received sodium thiopental intraperitoneally and were randomly allocated into 4 subgroups: (1) nonventilated (n = 4) for molecular biology analysis only (control); (2) sodium thiopental (n = 8); (3) propofol (n = 8); and (4) dexmedetomidine (n = 8), which received continuous IV administration of the corresponding agents and were mechanically ventilated (tidal volume = 6 mL/kg body weight, fraction of inspired oxygen = 0.4, positive end-expiratory pressure = 3 cm H2O) for 1 hour. RESULTS:Compared with lean animals, obese rats did not present increased body weight but had higher total body and trunk fat percentages, airway resistance, and interleukin-6 levels in the lung tissue (P = 0.02, P = 0.0027, and P = 0.01, respectively). In obese rats, propofol, but not dexmedetomidine, yielded increased airway resistance, bronchoconstriction index (P = 0.016, P = 0.02, respectively), tumor necrosis factor-&agr;, and interleukin-6 levels, as well as lower levels of nuclear factor-erythroid 2–related factor-2 and glutathione peroxidase (P = 0.001, Bonferroni-corrected t test). CONCLUSIONS:In this model of diet-induced obesity, a 1-hour propofol infusion yielded increased airway resistance, atelectasis, and lung inflammation, with depletion of antioxidative enzymes. However, unlike sodium thiopental and propofol, short-term infusion of dexmedetomidine had no impact on lung morphofunctional and biological variables.

Immunomodulation after ischemic stroke: potential mechanisms and implications for therapy

Brain injuries are often associated with intensive care admissions, and carry high morbidity and mortality rates. Ischemic stroke is one of the most frequent causes of injury to the central nervous system. It is now increasingly clear that human stroke causes multi-organ systemic disease. Brain inflammation may lead to opposing local and systemic effects. Suppression of systemic immunity by the nervous system could protect the brain from additional inflammatory damage; however, it may increase the susceptibility to infection. Pneumonia and urinary tract infection are the most common complications occurring in patients after stroke. The mechanisms involved in lung-brain interactions are still unknown, but some studies have suggested that inhibition of the cholinergic anti-inflammatory pathway and release of glucocorticoids, catecholamines, and damage-associated molecular patterns (DAMPs) are among the pathophysiological mechanisms involved in communication from the ischemic brain to the lungs after stroke. This review describes the modifications in local and systemic immunity that occur after stroke, outlines mechanisms of stroke-induced immunosuppression and their role in pneumonia, and highlights potential therapeutic targets to reduce post-stroke complications. Despite significant advances towards a better understanding of the pathophysiology of ischemic stroke-induced immunosuppression and stroke-associated pneumonia (SAP) in recent years, many unanswered questions remain. The true incidence and outcomes of SAP, especially in intensive care unit settings, have yet to be determined, as has the full extent of stroke-induced immunosuppression and its clinical implications.