Introduction
Diabetes injures almost all human organs, and the lung is one of the target viscera, which was first reported by Schuyler et al.1 The present study aimed to reveal the anti-inflammatory effect of ghrelin on diabetic lung disease both in vivo and in vitro, and to discuss its probable molecular mechanism. The structural and physiological abnormalities of the lung have been observed, and severe damage to lung function has been found in patients with diabetes.2 Patients with diabetes have lower pulmonary microvascular distensibility in microvascular complications,3 and these features are also related to pulmonary hypertension.4 5 The newest study demonstrated that patients with diabetes tend to be infected with COVID-19 compared with patients without non-diabetes.6 7 Despite the evidence of the diabetic lung disease, the specific molecular mechanism remains unclear. Therefore, more research is urgently needed to clarify the process of diabetic lung disease. In our previous research, we demonstrated that high glucose (HG) could induce epithelial cell death in the lungs in vitro, but the relative phenomenon in vivo still needs to be investigated.8
As a well-known orexigenic peptide, ghrelin is derived predominantly in the gastric area and is also found in the lungs, heart and lymph nodes.9 It was demonstrated previously that ghrelin has an anti-inflammatory effect10 in addition to its growth hormone-releasing properties. Furthermore, it was reported that ghrelin could protect lungs from diseases.11 12 To suppress the activity of ghrelin, D-lys-3-GHRP-6 (an antagonist of ghrelin) is often used in studies in vivo and in vitro.13 14 Our previous studies found that ghrelin could attenuate 16HBE apoptosis induced by HG by regulating the Wnt/β-catenin pathway.8 However, it is still unknown whether other pathways participate in this process.
Increasing evidence indicates that inflammatory mechanisms play a key role in the occurrence and development of diabetes and its complications.15 The Toll-like receptor 4 (TLR4) pathway is closely related to the inflammatory process. The stimulation of TLR4 might activate MyD88 via a series of cascade reactions and contact the promoters of proinflammatory genes. These promoters might activate gene expression and stimulate the inflammatory response, and many cytokines are released to stimulate the occurrence of inflammation.16 Recent studies have investigated the function of the TLR4 pathway in lung diseases.17 Lu et al18 recently found that cyclic peptide extracts relieved the symptoms of chronic obstructive pulmonary disease (COPD) via TLR4 signaling.
Diabetic lung disease is a diabetes complication that occurs in the respiratory system, but this illness is always neglected, and there are few reports on it. In this study, we speculated that hyperglycemia could induce inflammation in diabetic lung disease, which might explain the increased pulmonary-related morbidity and mortality in diabetes. To verify this conjecture, we used streptozotocin (STZ) mice as the diabetic animal model in vivo and human bronchial epithelial cells (16HBE) as the lung cell model in vitro. We explored whether ghrelin could alleviate the stimulation of TLR4 caused by hyperglycemia (or HG), and changes in inflammatory cytokines in diabetic lungs were also detected.