Diabetic Microvascular Disease and Pulmonary Fibrosis: The Contribution of Platelets and Systemic Inflammation

Abstract

Diabetes is strongly associated with systemic inflammation and oxidative stress, but its effect on pulmonary vascular disease and lung function has often been disregarded. Several studies identified restrictive lung disease and fibrotic changes in diabetic patients and in animal models of diabetes. While microvascular dysfunction is a well-known complication of diabetes, the mechanisms leading to diabetes-induced lung injury have largely been disregarded. We described the potential involvement of diabetes-induced platelet-endothelial interactions in perpetuating vascular inflammation and oxidative injury leading to fibrotic changes in the lung. Changes in nitric oxide synthase (NOS) activation and decreased NO bioavailability in the diabetic lung increase platelet activation and vascular injury and may account for platelet hyperreactivity reported in diabetic patients. Additionally, the Janus kinase/signal transducer and activator of transcription (JAK/STAT) pathway has been reported to mediate pancreatic islet damage, and is implicated in the onset of diabetes, inflammation and vascular injury. Many growth factors and diabetes-induced agonists act via the JAK/STAT pathway. Other studies reported the contribution of the JAK/STAT pathway to the regulation of the pulmonary fibrotic process but the role of this pathway in the development of diabetic lung fibrosis has not been considered. These observations may open new therapeutic perspectives for modulating multiple pathways to mitigate diabetes onset or its pulmonary consequences.

Breathlessness and Restrictive Lung Disease: An Important Diabetes-Related Feature in Patients with Type 2 Diabetes

“…The common hypothesis regarding pulmonary fibrosis involves oxidative stress, endothelial microinjuries, and platelet activation with consecutive inflammation [6]. Similar mechanisms have been described in diabetes-related complications, especially nephropathy [5, 6, 40, 41]. Furthermore, low estimated glomerular filtration rate was associated with decreased survival in patients with IPF [42].…”

Pulmonary vascular dysfunction in metabolic syndrome

“…; Jagadapillai et al . ; Papinska et al . ), suggesting that inflammation might be occurring in the pulmonary vasculature.…”

Parkinson’s disease: a systemic inflammatory disease accompanied by bacterial inflammagens

“…When these inflammatory molecules disrupt endothelial cell structure, the endothelial cells release collagen and von Willebrand (vWF). vWF is also a mediator of vascular inflammation (Gragnano et al, 2017), and it binds to exposed collagen and anchors platelets to the subendothelium (Du, 2007), causing platelet aggregation (Xu et al, 2016), and formation of a platelet plug (Jagadapillai et al, 2016). Both collagen and vWF act as platelet receptor ligands, causing platelet outside-in signaling, followed by inside-out signaling.…”