Lung function in murine models of asthma, emphysema and pulmonary fibrosis

J.L. Pype1, H. Xu1, Y.Y. Verheyden1, M.A. Devlieghere1, K.T. Meurrens1, M.J. Peck2 and P.M. Vanscheeuwijck1. Philip Morris Research Laboratories bvba, 3001 Leuven, Belgium1, Philip Morris Research Laboratories GmbH, Cologne, Germany2.

Pulmonary function tests are designed to identify and quantify abnormalities in the function of the respiratory system. Measuring lung function in mice is also essential for establishing the relevance of comparing murine models to human lung disease. The aim of the present study was to characterize lung dynamics in murine models of lung diseases, such as allergic asthma, emphysema and pulmonary fibrosis and to identify patterns of pulmonary function test abnormalities for these diseases.

• 1) allergic asthma (AA): Male BALB/c mice were i.p. sensitised with ovalbumin (500 μg/kg) in Al(OH)3 (4mg/ml) on day 1 and 5. On days 12, 15 and 16 the animals were intranasally challenged with saline (control animals) or ovalbumin (1mg/ml). 2) elastase-induced emphysema (EE) and bleomycin-induced pulmonary fibrosis (PF): Male C57BL/6 mice were treated with either saline, porcine pancreatic elastase (i.t. PPE, 1.5 or 3 mg/kg) or bleomycin (i.n., bleo, 2 U/kg). Lung function was measured on day 19 (AA) or 2 and 4 weeks after administration of elastase and bleomycin for EE and PF. Determination of
  
• 2) animals were anaesthetised (pentobarbital 75mg/kg, i.p.), tracheostomised and the trachea cannulated. Paralysis (pancuronium bromide 0.8 mg/kg, i.p.) was induced following connection of the cannula to a computer-controlled small animal ventilator (Flexivent, Scireq), which allowed the application of specific tailored volume perturbations to the lung. A positive end expiratory pressure of 3 cm H2O was applied.
  

No significant treatment-induced changes were seen in baseline values in AA. Data are mean ± SD of 7-13 animals (EE: PPE 3 mg/kg at 4 weeks, and PF: bleo 2U at 4 weeks). Statistical significant changes were found in tissue elastance (cm H2O/ml) in EE and PF (control: 25.53 ± 4.33, EE: 14.76 ± 2.05, p<0.001, PF: 46.04 ± 20.71, p<0.001). Dynamic and static compliances were changed accordingly. Tissue resistance (cm H2O/ml) was decreased in EE and increased in PF (control: 5.70 ± 1.04, EE: 4.30 ± 0.48, p<0.05, PF: 7.64 ± 2.25 p<0.05). Lung resistance and resistance of the central airways were changed accordingly. Maximal pressure (cm H2O) at total lung capacity was increased in PF (control: 37.8 ± 37, PF: 53.5 ± 9.8, p<0.01, not determined in EE) and maximal volume (ml) at a pressure of 30 cmH2O was decreased in PF (control, 0.737 ± 0.122, PF, 0.550 ± 0.128, p<0.001, not determined in EE). Pressure volume loops in EE were shifted to the left and in PF to the right while in AA only the inspiratory limb of the PV loop was shifted to the right.

We have demonstrated patterns of pulmonary function abnormalities for particular pulmonary diseases in mice that may help to identify different pathologies and thus increase their relevance to human diseases such as asthma and COPD.