Cyclophosphamide combined with methylprednisolone can play a therapeutic role by delaying the aging of pulmonary fibrosis

Abstract

Background: Aging is a natural process characterized by a progressive functional impairment and reduced capacity to respond adaptively to environmental stimuli.Idiopathic pulmonary fibrosis(IPF)has been found to increase considerably with age.Immunosenescence,oxidative stress,abnormal shortening of telomeres, apoptosis, and epigenetic changes affecting gene expression have been proposed to contribute to the aging process,and aging-associated diseases. The above indicates that aging can increase the incidence of IPF. So can the occurrence of aging be aggravated after IPF? We examined pathological damage, collagen deposition, oxidative stress and immunosenescence to determine whether bleomycin(BLM)-induced pulmonary fibrosis (PF) accelerates aging in rats. If so, what drugs can inhibit or delay this aging. In clinical studies,the combination of methylprednisolone(MP) and cyclophosphamide(CTX) has shown great benefits in patients with IPF, but its effect on aging resulting from fibrosis is not fully understood. Therefore, we investigated whether MP combined with CTX could delay or inhibit aging in IPF rats. It may provide new targets for the treatment of IPF. Methods: PF rat models were induced by BLM and treated with MP or MP/CTX combination.Transmission electron microscope, hematoxylin and eosin (H&E) and Masson staining were used to measure the morphology of PF. α-SMA and collagen I levels were examined by western blot and immunohistochemistry. Malondialdehyde(MDA),myeloperoxidase(MPO),lutathione peroxidase(GSH-PX) and superoxide dismutase(SOD) levels were determined using commercial kits.T cells were analyzed with flow cytometry. Results: We found that pathological damage, collagen deposition, oxidative stress, and T-cell senescence were increased after BLM-induced PF. The combined use of MP and CTX can alleviate pathological damage, reduce oxidative stress response, such as reducing MDA and MPO levels, and increasing SOD and GSH-PX activities. And inhibition of T cell senescence in lung tissue, such as reduction of CD27-CD28- CD4+ T cells in BLM-induced PF. Conclusions: BLM-induced PF aggravated the occurrence of aging in rats. The combination of MP and CTX can inhibit or delay aging, and thus play a therapeutic role in IPF.These findings provide new insights into the mechanism by which MP and CTX act in combination on IPF.