Metformin attenuates lead‐induced inflammatory and apoptotic lung injury through modulation of P53 and TNF‐α pathways in rats

Abstract

Exposure to heavy metals, such as Lead (Pb) is a matter of growing concern and potential risk factor for developing inflammatory lung diseases. The aim of this study was to a) investigate the protective effect of metformin against Pb‐induced lung injury in rat and b) investigate the underlying mechanisms specifically the role of oxidative stress, inflammation and apoptosis. For this purpose, twenty‐four adult male Wistar albino rats weighing about 230 gm were randomly distributed into six study groups of four rats each. The first group received normal saline (0.5 ml/kg/day) for 6 consecutive days and served as a a Control. The second group received metformin (500 mg/kg) for 6 consecutive days. The third and fourth groups received a single dose of normal saline (0.5 ml/kg/day) for 3 consecutive days followed by lead nitrate (Pb) (25 and 50 mg/kg, i.p.) for 3 consecutive days, respectively. The fifth and sixth groups received metformin (500 mg/kg) for 3 consecutive days followed by Pb 25 and 50 mg/kg, i.p. plus metformin 500 mg/kg for additional 3 consecutive days, respectively. One day after the last dose, animals were a and blood samples were collected via cardiac puncture for determination the levels of Pb. Rats lung tissues were excised and processed for histopathological examination, determination the levels of mRNA and protein expression of target genes, Analysis of apoptosis and TNF‐α production were determined by flow cytometer. Our results showed that exposure to Pb caused induction of inflammatory cells infiltration, cell apoptosis, modulation of genes involving in inflammation and oxidation, induction of p53 and TNF‐α were demonstrated in Pb‐induced lung injury. Administration of metformin 500 mg/kg for 6 days resulted in a protective effect on the Pb‐induced inflammatory lung injury through induction of the expression levels of NQO1, SOD, HO‐1, and p53 genes. In addition, metformin treatment significantly reduced the production of TNF‐α and expression of IL‐6 while induced the expression of IL‐10 in Pb‐treated groups. In conclusion, these observations suggest that metformin processes anti‐inflammatory, antiapoptotic and the induction of antioxidants properties against Pb‐induced lung injuries.