Bleomycin induces emphysema in α-PI deficient mice

In a recent study we investigated in mice the role of a genetic deficiency of serum α-PI on the development of the pulmonary damage induced by the fibrogenic agent bleomycin (BLM). As expected BLM administration to mice resulted in alveolitis and fibrosis. It also resulted in enlargement of air spaces that may be due to loss of alveolar septa and/or retraction forces caused by the fibrotic process. In this study we investigated whether BLM induces air spaces enlargements of destructive type in strains of mice with a genetic deficiency of their antielastase screen. We used Balb/c mice with normal levels of serum α1-PI (5.9±0.5 mg/ml); C57Bl/6J, which show intermediate levels (4.4±0.3, p<0.05), and pallid mice with the lowest values (2.7±0.4 p<0.05). Mice from all strains received either saline (50µl), or BLM (0.1U/50µl) intratracheally and were sacrificed at 1, and 3, 14, 21 and 35 days after the treatment. The lungs were assessed by means of biochemical, morphological and morphometrical methods. At 14 days fibrosis affected 23.46 ± 9.48 % (mean ± S.D) and 40.62 ± 13.34 % (p<0.01) of the lungs of C57Bl/6J and pallid mice, respectively. At this time, air spaces enlargements affected 3.68 ± 3.11 % and 12.57 ± 4.13 % (p<0.01) of lung in C57Bl/6J and pallid mice, respectively. On the other hand, Balb c mice showed negligible foci of cellular infiltration and fibrosis (2±1%) and no areas of air-space enlargements. Pallid and C57 mice, 21h and 3 days after BLM, showed spotty areas of inflammatory cells infiltration and appreciable emphysematous changes. These changes that appeared long before the development of fibrosis, were associated with a decrease in lung desmosine content and an increase interstitial elastase burden. At 21 and 35 days after BLM, both the emphysematous and fibrotic lesions were more severe, and intermixed. At these times, the emphysematous changes became of paracicatricial type. In conclusion, the data reported strongly suggest that the air-space enlargements observed in mice with a genetic deficiency of serum α-PI, early after BLM, represent areas of true emphysema caused by a proteolytic attack from infiltrating inflammatory cells. The further deterioration of these changes evident at the later times after BLM treatment can be ascribed to the retraction forces of the fibrotic process.