The role of mast cells and macrophages in amiodarone induced pulmonary fibrosis and the possible attenuating role of atorvastatin

Abstract

Amiodarone (AM) is an effective anti-arrhythmic drug. We investigated the role of mast cells and macrophages on AM induced pulmonary fibrosis and the action of atorvastatin on this fibrosis. Rats were allocated into four groups; negative control (1), positive control (2), 30 mg/kg body weight/day AM (3) and AM + 10 mg/kg/day atorvastatin (4). Lungs were harvested and prepared for histology and immunohistochemistry. Hematoxylin and eosin stained sections of group 3 exhibited disorganized lung architecture. We found cellular debris in the lumen of both intrapulmonary bronchi and bronchioles with partial disruption of the thickened epithelial lining and mononuclear cellular infiltration into the lamina propria. We also observed thickening of the epithelial lining and the smooth muscle layer. Congested, dilated and thickened blood capillaries and thickened inter-alveolar septa were observed with mononuclear cellular infiltrates in the lung of group 3. Most alveoli were collapsed, but some dilated ones were detected. In some alveoli, type ІІ pneumocytes were increased, while type I cells were decreased. We observed significant increases in the amount of collagen in the thickened inter-alveolar septa, around bronchioles and around blood capillaries in sections from group 3. We found a significant increase in mast cells and alveolar macrophages in group 3 compared to group 1. Mast cells and macrophages appear to play important roles in AM induced pulmonary fibrosis. Atorvastatin appears to attenuate this condition.

Different Sensitivity of Macrophages to Phospholipidosis Induction by Amphiphilic Cationic Drugs

“…Not only lysosomes but also cell size (area) was determined because it has been reported that amiodarone increases the number and size of alveolar macrophages in rats [26]. In our study, both CADs at concentrations ≥2.5 µM increased the cell area of M1 macrophages, at ≥5 µM the area of RAW264.7 cells, and at 10 µM the area of THP-1 cells.…”

LDLR dysfunction induces LDL accumulation and promotes pulmonary fibrosis

“…An increasing body of evidence has indicated that statins may have a beneficial effect on clinical outcomes in PF and even in COVID‐19 23,36–38 . By searching all the literature investigating the association of statins with PF, including 7 clinical studies 23,24,39–43 and 18 experimental studies, 24,36,44–59 we found that almost all studies trends to indicate that the statins are protective for PF (Supporting information Table S3). It is believed that lipophilic statins are taken up faster by PF lung tissue through passive diffusion than through active uptake 60 .…”

Progress of Statin Therapy in the Treatment of Idiopathic Pulmonary Fibrosis

“…In another study, researchers found that simvastatin protected the endothelial barrier by inhibiting NOX activity and superoxide production [ 98 ]. El-Mohandes et al found that amiodarone was capable of inducing the generation of degranulated mast cells and alveolar macrophages in alveolar sacs, and the administration of atorvastatin significantly reduced the number of mast cells and alveolar macrophages and inhibited pulmonary fibrosis in rats [ 99 ]. Mast cell granules contain histamine and TGF- β ; following degranulation, the components can promote the proliferation of fibroblasts, and alveolar macrophages can also secrete TGF- β , thereby promoting the enhancement of collagen fiber synthesis and leading to the deposition of ECM [ 100 ].…”