Sergio P. Ribeiro

Injurious ventilatory strategies increase cytokines and c-fos m-RNA expression in an isolated rat lung model.

We examined the effect of ventilation strategy on lung inflammatory mediators in the presence and absence of a preexisting inflammatory stimulus. 55 Sprague-Dawley rats were randomized to either intravenous saline or lipopolysaccharide (LPS). After 50 min of spontaneous respiration, the lungs were excised and randomized to 2 h of ventilation with one of four strategies: (a) control (C), tidal volume (Vt) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H2O; (b) moderate volume, high PEEP (MVHP), Vt = 15 cc/kg; PEEP = 10 cm H2O; (c) moderate volume, zero PEEP (MVZP), Vt = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), Vt = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFalpha, IL-1beta, IL-6, IL-10, MIP-2, and IFNgamma were measured by ELISA. Zero PEEP in combination with high volume ventilation (HVZP) had a synergistic effect on cytokine levels (e.g., 56-fold increase of TNFalpha versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three-fold increase in TNFalpha, whereas MVZP produced a six-fold increase in lavage TNFalpha. Northern blot analysis revealed a similar pattern (C, MVHP < MVZP < HVZP) for induction of c-fos mRNA. These data support the concept that mechanical ventilation can have a significant influence on the inflammatory/anti-inflammatory milieu of the lung, and thus may play a role in initiating or propagating a local, and possibly systemic inflammatory response.

Induction of the heat shock response reduces mortality rate and organ damage in a sepsis-induced acute lung injury model.

ObjectiveTo test the hypothesis that induction of heat shock proteins before the onset of sepsis could prevent or reduce organ injury and death in a rat model of intra-abdominal sepsis and sepsis-induced acute lung injury produced by cecal ligation and perforation. DesignProspective, blind, randomized, controlled trial. SettingUniversity research laboratory. SubjectsOne-hundred forty-two adult Sprague-Dawley rats (weight range 200 to 300 g). InterventionsProduction of intra-abdominal sepsis and exposure to heat stress. Animals were randomly divided into four groups: heated and septic, heated and sham-septic, unheated and septic, and unheated and sham-septic. Measurements and Main ResultsWe evaluated the mortality rate and pathologic changes in lung, heart, and liver at 18 hrs after cecal perforation, at 24 hrs after removal of the cecum, and at 7 days after perforation. Heated animals exhibited a maximum increase in heat shock protein of 72 kilodalton molecular weight protein concentrations in the lungs and heart 6 to 24 hrs after the hyperthermic stress. By 18 hrs after perforation, 25% of the septic, unheated animals had died whereas none of the septic heated animals had died (p < .005). Septic, heated animals showed a marked decrease in 7-day mortality rate (21%) compared with septic unheated animals (69%) (p < .01). Furthermore, septic heated animals showed less histologic evidence of lung and liver damage than septic unheated animals. ConclusionsThese data suggest that thermal pretreatment, associated with the synthesis of heat shock proteins, reduces organ damage and enhances animal survival in experimental sepsis-induced acute lung injury. Although the mechanisms by which heat shock proteins exert a protective effect are not well understood, these data raise interesting questions regarding the importance of fever in the protection of the whole organism during bacterial infection. (Crit Care Med 1994; 22:914–921)

Sodium arsenite induces heat shock protein-72 kilodalton expression in the lungs and protects rats against sepsis

ObjectiveTo examine the hypothesis that induction of heat shock proteins by a non-thermal mechanism would confer protection against experimental sepsis. DesignProspective, blind, randomized, laboratory study. SettingUniversity research laboratory. SubjectsSixty-two adult male Sprague-Dawley rats (weight range 250 to 350 g). InterventionsAdministration of sodium arsenite or saline in an animal model of sepsis by cecal ligation and perforation. Measurements and Main ResultsSixty-two rats were randomly divided into two groups: group 1 received sodium arsenite (6 mg/kg iv) and group 2 received saline injection, in a blinded fashion. Eighteen hours after receiving sodium arsenite or saline, cecal ligation and perforation were performed and the animals were monitored for mortality for 96 hrs. Sodium arsenite injection, in the absence of an increase in body temperature, induced heat shock protein of 72-kilodalton molecular weight expression in the lung, which was detected 2 hrs after injection, peaked between 9 and 24 hrs, and returned to baseline by 48 hrs. Prior administration of sodium arsenite conferred significant protection against cecal ligation and perforation-induced mortality at 18 hrs (p = .002) and 24 hrs (p = .026) after cecal ligation and perforation, and correlated with expression of heat shock proteins in the lungs. However, at 48 and 96 hrs, when heat shock protein expression returned to basal values, the mortality rates of both groups were indistinguishable. ConclusionsWe conclude that in vivo injection of sodium arsenite induces expression of HSP-72 in the lungs, and confers transient protection against experimental sepsis during the period that heat shock proteins are also expressed. (Crit Care Med 1994; 22:922–929)