Effect of leflunomide [avara] drug on the lung of adult male albino rats: a histological and immunohistochemical study

ABSTRACT

Leflunomide is a newly developed disease-modifying antirheumatic drug. Recently, spontaneous reports of interstitial lung disease in patients treated with leflunomide have been reported. It is unclear whether leflunomide is directly related to the occurrence of such lung toxicity or whether other factors might be involved. This study was carried out to demonstrate the effect of leflunomide on the lung structure and the possibility of recovery after its withdrawal. Thirty adult male albino rats were used and were divided into three main groups [10 animals each]; a control group, leflunomide treated group which received 2 mg/kg body weight of leflunomide orally once daily for 8 weeks, and the third group received the same dose of leflunomide as the second group then the drug was stopped for 4 weeks. Lung specimens were processed for histological study by LM and EM and stained immunohistochemically by caspase-3 antibody for detection of apoptotic cells. In leflunomide treated rats the lung showed significant increase in the thickness of the inter-alveolar septa with mononuclear cellular infiltration associated with alveolar damage and many collapsed alveoli. Significant increase in caspase- 3 positive alveolar cells was detected. Type II pneumocytes were significantly increased in number with increase in the collagen content of the inter-ale veolar septa when compared with the control group. Ultrastructurally, degenerative changes were observed in the alveolar cells in the form of cytoplasamic vacuolation, mitochondrial degeneration and destruction of lamellar bodies. After stoppage of leflunomide treatment, these changes in lung structure showed partial recovery with persistence of lung fibrosis suggesting that the lung toxicity of leflunomide was partially reversible. Leflunomide could induce alveolar damage and pulmonary fibrosis and it is recommended that patients under leflunomide treatment should be regularly examined for early detection of interstitial pneumonitis