Injurious Ventilatory Strategies Increase Cytokines and C-Fos m-RNA Expression in an Isolated Rat Lung Model

J Clin Invest. 1997 Mar 1;99(5):944-52. doi: 10.1172/JCI119259.

Abstract

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.

Publication types

  • Clinical Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Northern
  • Bronchoalveolar Lavage Fluid / chemistry
  • Chemokine CCL4
  • Enzyme-Linked Immunosorbent Assay
  • Genes, fos
  • Inflammation / immunology
  • Interferon-gamma / analysis
  • Interferon-gamma / immunology
  • Interleukin-1 / analysis
  • Interleukin-1 / immunology
  • Interleukin-10 / analysis
  • Interleukin-10 / immunology
  • Interleukin-6 / analysis
  • Interleukin-6 / immunology
  • Lipopolysaccharides / pharmacology
  • Lung / immunology*
  • Lung / pathology*
  • Lung Compliance
  • Macrophage Inflammatory Proteins / analysis
  • Macrophage Inflammatory Proteins / immunology
  • Male
  • Positive-Pressure Respiration / adverse effects*
  • Positive-Pressure Respiration / methods
  • Proteins / analysis
  • RNA, Messenger / analysis
  • Rats
  • Rats, Sprague-Dawley
  • Tumor Necrosis Factor-alpha / analysis
  • Tumor Necrosis Factor-alpha / immunology

Substances

  • Chemokine CCL4
  • Interleukin-1
  • Interleukin-6
  • Lipopolysaccharides
  • Macrophage Inflammatory Proteins
  • Proteins
  • RNA, Messenger
  • Tumor Necrosis Factor-alpha
  • Interleukin-10
  • Interferon-gamma