Exposure to mechanical ventilation promotes tolerance to ventilator-induced lung injury by Ccl3 downregulation

Am J Physiol Lung Cell Mol Physiol. 2015 Oct 15;309(8):L847-56. doi: 10.1152/ajplung.00193.2015. Epub 2015 Aug 21.


Inflammation plays a key role in the development of ventilator-induced lung injury (VILI). Preconditioning with a previous exposure can damp the subsequent inflammatory response. Our objectives were to demonstrate that tolerance to VILI can be induced by previous low-pressure ventilation, and to identify the molecular mechanisms responsible for this phenomenon. Intact 8- to 12-wk-old male CD1 mice were preconditioned with 90 min of noninjurious ventilation [peak pressure 17 cmH2O, positive end-expiratory pressure (PEEP) 2 cmH2O] and extubated. Seven days later, preconditioned mice and intact controls were submitted to injurious ventilation (peak pressure 20 cmH2O, PEEP 0 cmH2O) for 2 h to induce VILI. Preconditioned mice showed lower histological lung injury scores, bronchoalveolar lavage albumin content, and lung neutrophilic infiltration after injurious ventilation, with no differences in Il6 or Il10 expression. Microarray analyses revealed a downregulation of Calcb, Hspa1b, and Ccl3, three genes related to tolerance phenomena, in preconditioned animals. Among the previously identified genes, only Ccl3, which encodes the macrophage inflammatory protein 1 alpha (MIP-1α), showed significant differences between intact and preconditioned mice after high-pressure ventilation. In separate, nonconditioned animals, treatment with BX471, a specific blocker of CCR1 (the main receptor for MIP-1α), decreased lung damage and neutrophilic infiltration caused by high-pressure ventilation. We conclude that previous exposure to noninjurious ventilation induces a state of tolerance to VILI. Downregulation of the chemokine gene Ccl3 could be the mechanism responsible for this effect.

Keywords: chemokines; genomics; immunotolerance; ventilator-induced lung injury.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Chemokine CCL3 / genetics*
  • Down-Regulation
  • Immune Tolerance
  • Lung / drug effects
  • Lung / immunology
  • Lung / pathology
  • Male
  • Mice
  • Phenylurea Compounds / pharmacology
  • Piperidines / pharmacology
  • Positive-Pressure Respiration / adverse effects
  • Receptors, CCR1 / antagonists & inhibitors
  • Respiration, Artificial / adverse effects*
  • Ventilator-Induced Lung Injury / genetics
  • Ventilator-Induced Lung Injury / immunology*
  • Ventilator-Induced Lung Injury / prevention & control*


  • Ccl3 protein, mouse
  • Ccr1 protein, mouse
  • Chemokine CCL3
  • Phenylurea Compounds
  • Piperidines
  • Receptors, CCR1
  • BX 471