Production of inflammatory cytokines in ventilator-induced lung injury: A reappraisal

We investigated the production of proinflammatory cytokines by the lung dur ing high mechanical stretch in vivo. To do this, we subjected rats to high- volume (42 ml/kg tidal volume [VT]) ventilation for 2 h. The animals develo ped severe pulmonary edema and alveolar flooding, with a high protein conce ntration in bronchoalveolar ravage fluid (BALF). The animals' BALF containe d no tumor necrosis factor (TNF)-alpha, negligible amounts of interleukin ( IL)-1 beta, and less than 300 pg/ml of the chemokine macrophage inflammator y protein (MIP)-2, an amount similar to that found in rats ventilated with 7 ml/kg VT. Systemic cytokine levels were below the detection threshold. Be cause isolated lungs have been shown to produce high levels of proinflammat ory cytokines when ventilated with a similarly high VT for the same duratio n (Tremblay, et al. J Clin Invest 1997;99:944-952), we reconsidered this sp ecific issue. We ventilated isolated, unperfused rat lungs for 2 h with 7 m l/kg or 42 ml/kg VT, Or maintained them in a statically inflated state. Neg ligible amounts of TNF-alpha were found in the BALF whatever the ventilator y condition applied. The BALF IL-1 beta concentration was slightly elevated and higher in lungs ventilated with 42 ml/kg VT than in those ventilated w ith 7 ml/kg VT or in statically inflated lungs (p < 0.05). The BALF MIP-2 c oncentration was moderately elevated in all isolated lungs (200 to 300 pg/m l), and was slightly higher (p < 0.05) in lungs ventilated with 42 ml/kg VT . After lipopolysaccharide (LPS) challenge, high levels of TNF-alpha, IL-1 beta, and MIP-2 were found in the animals' plasma before the lungs were rem oved. Negligible amounts of TNF-alpha and IL-1 beta were retrieved from the BALF of statically inflated lungs. The concentrations of TNF-alpha and IL- 1 beta were higher in the BALF of ventilated lungs (p < 0.001). The TNF-<al pha>. level did not differ with the magnitude of VT, whereas the level of I L-1 beta was significantly higher in BALF of lungs ventilated with 42 ml/kg VT (p < 0.01). The MIP-2 concentrations were similar for the two ventilato ry conditions. These results suggest that ventilation that severely injures lungs does not lead to the release of significant amounts of TNF-<alpha> o r IL-1 beta by the lung in the absence of LPS challenge but may increase lu ng MIP-2 production.