Lung Injury Commonly Induced by Pyrrolizidine Alkaloids

Abstract

Pyrrolizidine alkaloids (PAs) are widely distributed natural toxins and extensively studied for their hepatotoxicity. However, PA-induced pulmonary toxicity and the underlying mechanism remain largely unknown. In our previous study, we have demonstrated that pneumotoxicity was commonly induced by retronecine and otonecine types PAs. Besides, using mice with conditional cytochrome P450 reductase gene deletion, we demonstrated that hepatic CYPs, but not extrahepatic CYPs, are essential for metabolic activation of PAs, and the reactive PA metabolites were carried by red blood cells (RBCs) and transported to the lungs to cause pneumotoxicity. In the present study, we investigated the role of RBCs in PA-induced pneumotoxicity. Rats were treated with retrorsine (RTS) and monocrotaline (MCT), two representative PAs. Compared with normally oxygenated RBCs from control rats, RBC collected from RTS and MCT-treated rats demonstrated significant morphological changes represented by loss of central concave, macrocytosis and agglutination, indicating possible functional changes of RBCs. Further, Raman spectrometry was applied to exam the functional changes of heme groups which are the major oxygen carrier protein in RBCs. Compared with wavenumbers of characteristic bands of oxygenated and deoxygenated RBCs of control rats, no differences were observed in RBCs obtained from RTS and MCT-treated rats, suggesting no changes in primary structure of heme. While, the intensities of the characteristic bands in RBCs obtained from MCT and RTS-treated rats fell between oxygenated RBCs and deoxygenated RBCs, indicating that both toxic PAs caused decrease in oxygen-carrying capability of RBCs. Our finding revealed that PAs decreased oxygen-carrying capability of RBCs and induced hypoxemia microenvironment, which may play an important role in PA-induced lung injury.