title: Influenza A H1N1 induces declines in alveolar gas exchange in mice consistent with rapid post-infection progression from acute lung injury to ARDS.
abstract: BACKGROUND
  Patients with severe seasonal or pandemic influenza pneumonia frequently develop acute respiratory distress syndrome (ARDS). One clinical diagnostic criterion for ARDS is the P(a)O(2):F(i)O(2) ratio, which is an index of alveolar gas exchange. However, effects of H1N1 influenza infection on P(a)O(2):F(i)O(2) ratios and related pathophysiologic readouts of lung function have not been reported in mice.
  
  
  METHODS
  To develop a method for determining P(a)O(2):F(i)O(2) ratios, uninfected mice were anesthetized with pentobarbital, diazepam/ketamine, or inhaled isoflurane. Subsequently, they were allowed to breathe spontaneously or were mechanically ventilated. After 15 minutes exposure to room air (F(i)O(2) = 0·21) or 100% O(2) (F(i)O(2) = 1·0), carotid P(a)O(2) was measured. To determine influenza effects on P(a)O(2):F(i)O(2), mice were challenged with 10,000 p.f..u./mouse influenza A/WSN/33.
  
  
  RESULTS
  P(a)O(2):F(i)O(2) ratios were abnormally low (≤400 mmHg) in spontaneously breathing mice. Mechanical ventilation with positive end-expiratory pressure was required to obtain P(a)O(2):F(i)O(2) ratios in uninfected mice consistent with normal values in humans (≥600 mmHg). At day 2 following infection P(a)O(2):F(i)O(2) ratios indicated the onset of acute lung injury. By day 6, P(a)O(2):F(i)O(2) ratios were <200 mmHg, indicating progression to ARDS. Impaired gas exchange in influenza-infected mice was accompanied by progressive hemoglobin desaturation, hypercapnia, uncompensated respiratory acidosis, hyperkalemia, and polycythemia.
  
  
  CONCLUSIONS
  Influenza infection of mice results in impairment of alveolar gas exchange consistent with rapid development of acute lung injury and progression to ARDS. P(a)O(2):F(i)O(2) ratios may be of utility as clinically relevant and predictive outcome measures in influenza pathogenesis and treatment studies that use mouse models.
authors.affiliation: Department of Veterinary Biosciences, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Zachary P
authors.initials: ZP
authors.lastname: Traylor
authors.forename: Famke
authors.initials: F
authors.lastname: Aeffner
authors.forename: Ian C
authors.initials: IC
authors.lastname: Davis
mesh_terms: D055371:Acute Lung Injury / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D015536:Down-Regulation; D005260:Female; D006801:Humans; D053118:Influenza A Virus, H1N1 Subtype / Q000502:physiology*; D007251:Influenza, Human / Q000150:complications* / Q000503:physiopathology / Q000821:virology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011650:Pulmonary Alveoli / Q000503:physiopathology* / Q000821:virology; D011659:Pulmonary Gas Exchange; D012128:Respiratory Distress Syndrome / Q000175:diagnosis / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology