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 (V(t)) = 7 cc/kg, positive end expiratory pressure (PEEP) = 3 cm H₂O; (b) moderate volume, high PEEP (MVHP), V(t) = 15 cc/kg; PEEP = 10 cm H₂O; (c) moderate volume, zero PEEP (MVZP), V(t) = 15 cc/kg, PEEP = 0; or (d) high volume, zero PEEP (HVZP), V(t) = 40 cc/kg, PEEP = 0. Ventilation with zero PEEP (MVZP, HVZP) resulted in significant reductions in lung compliance. Lung lavage levels of TNFα, IL- 1β, IL-6, IL-10, MIP-2, and IFNγ 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 TNFα versus controls). Identical end inspiratory lung distention with PEEP (MVHP) resulted in only a three- fold increase in TNFα, whereas MVZP produced a six-fold increase in lavage TNFα. 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.