title: Hypercapnic acidosis attenuates the pulmonary innate immune response in ventilated healthy mice.
abstract: BACKGROUND
  Mechanical ventilation with small tidal volumes reduces the development of ventilator-induced lung injury and mortality, but may increase PaCO2. It is not clear whether the beneficial effect of a lung-protective strategy results from reduced ventilation pressures/tidal volumes or is mediated by the effects of hypercapnic acidosis on the inflammatory response involved in the pathogenesis of ventilator-induced lung injury.
  
  
  OBJECTIVE
  To analyze whether hypercapnic acidosis affects lung tissue cytokine levels and leukocyte influx in healthy ventilated mice.
  
  
  METHODS
  Analysis of lung tissue and plasma concentrations of interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, IL-6, IL-10, and keratocyte-derived chemokine after 2 hrs of mechanical ventilation (V(t) 8 mL/kg, positive end-expiratory pressure 4 cm H2O) with 0.06% CO2 (room air), 2% CO2, or 4% CO2.
  
  
  METHODS
  Healthy C57BL6 mice (n = 40).
  
  
  RESULTS
  PaCO2 and pH were within normal range when ventilated with 0.06% CO2 and significantly changed with 2% and 4% CO2: (mean +/- SD) pH 7.23 +/- 0.06 and 7.15 +/- 0.04, PaCO2 7.9 +/- 1.4 and 10.8 +/- 0.7 kPa, respectively (p < 0.005). Blood pressure remained within normal limits in all animals. Quantitative microscopic analysis showed a 4.7 +/- 3.7-fold increase (p < 0.01) in pulmonary leukocyte influx in normocapnic ventilated animals and a significant reduction in leukocyte influx of 57 +/- 32% (p < 0.01) and 67 +/- 22% (p < 0.01) when ventilated with 2% and 4% CO2, respectively. Normocapnic ventilation induced a significant elevation of lung tissue IL-1beta (1516 +/- 119 ng/mL), TNF-alpha (344 +/- 88 ng/mL), IL-6 (6310 +/- 807 ng/mL), IL-10 (995 +/- 152 ng/mL), and keratocyte-derived chemokine (36,966 +/- 15,294 ng/mL) (all p-values <0.01). Hypercapnic acidosis with 2% respectively 4% CO2 significantly attenuated this increase with 25 +/- 32% and 54 +/- 32% (IL-1beta, p < 0.01); 17 +/- 36% and 58 +/- 33% (TNF-alpha, p < 0.02); 22 +/- 34% and 89 +/- 6% (IL-6, p < 0.01); 20 +/- 31% and 67 +/- 17% (IL-10, p < 0.01) and 16 +/- 44% and 45 +/- 30% (keratocyte-derived chemokine, p = 0.07).
  
  
  CONCLUSIONS
  Hypercapnic acidosis attenuates the mechanical ventilation-induced immune response independent from reduced tidal volumes/pressures and may protect the lung from ventilator induced lung injury.
authors.affiliation: Maxima Medical Centre, Veldhoven, The Netherlands. f.halbertsma@mmc.nl
authors.forename: Feico J J
authors.initials: FJ
authors.lastname: Halbertsma
authors.forename: Michiel
authors.initials: M
authors.lastname: Vaneker
authors.forename: Peter
authors.initials: P
authors.lastname: Pickkers
authors.forename: Dirk G
authors.initials: DG
authors.lastname: Snijdelaar
authors.forename: Jan
authors.initials: J
authors.lastname: van Egmond
authors.forename: Gert J
authors.initials: GJ
authors.lastname: Scheffer
authors.forename: Hans G
authors.initials: HG
authors.lastname: van der Hoeven
mesh_terms: D000138:Acidosis / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001784:Blood Gas Analysis; D016207:Cytokines / Q000378:metabolism*; D007962:Leukocytes / Q000378:metabolism*; D008168:Lung / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D012121:Respiration, Artificial / Q000009:adverse effects; D013990:Tidal Volume
chemical_list: D016207:Cytokines