Delayed lymphoid lung infiltration induced by cyclophosphamide in rats

The pulmonary toxicity of antineoplastic drugs may be either direct or mediated by hypersensitivity. The aim of this study was to determine whether the mechanism by which cyclophosphamide (CY) damages the lung is direct and immediate or is the result of delayed immune toxicity. Pulmonary and immune changes following intraperitoneal injection of either CY (50 mg/kg) or NaCl (0.9%) in rats were assessed repeatedly over a period of 31 days by semi-quantitative histological studies, by measuring the pulmonary water/body weight ratio, dry lung weight/body weight ratio, heart weight and by assessing the transfer of [125I]-albumin in lung tissue. Lung damage was delayed and greatest at 11 (D11) and 14 (D14) days after CY injection. The pulmonary lesions were: (i) an infiltration of lymphocytes, plasma cells and histiocytes surrounding blood vessels and small airways, (ii) an alveolitis composed of macrophages, lymphocytes, a few neutrophils and a lymphoid infiltration of alveolar septa. Pulmonary water/body weight and dry lung weight/body weight ratios also increased and peaked at D11-D14 in CY-treated rats. No significant increase in [125I]-albumin in lung tissue or in heart weight was observed. It can be concluded that the mechanism by which CY induces a lymphoid lung infiltration is not direct and immediate but is the result of a delayed immune toxicity.