Abstract
Diminished lymphatic function and abnormal morphology are common in chronic inflammatory diseases. Recent studies are investigating whether it is possible to target chronic inflammation by promoting resolution of inflammation, in order to enhance lymphatic function and attenuate disease. Resolution of inflammation is an active process regulated by bioactive lipids known as specialized pro-resolving mediators (SPMs). SPMs can modulate leukocyte migration and function, alter cytokine/chemokine release, modify autophagy, among other immune-related activities. Here, we summarize the role of the lymphatics in resolution of inflammation and lymphatic impairment in chronic inflammatory diseases. Furthermore, we discuss the current literature describing the connection between SPMs and the lymphatics, and the possibility of targeting the lymphatics with innovative SPM therapy to promote resolution of inflammation and mitigate disease.
Highlights
This review provides an overview of the abundance, and the effects of specialized pro-resolving mediators (SPMs) on the lymphatic system in relation to inflammatory diseases such as cardiovascular disease, acute respiratory distress syndrome, inflammatory bowel disease (IBD) and dry eye disease (DED)
Stimulating lymphangiogenesis by treating plaque prone mice (LDL receptor knockout on a high fat diet) with vascular endothelial growth factor (VEGF)-C led to improved lymphatic molecular transport, reduced plaque formation, limited macrophage accumulation and enhanced immune cell migration through the lymphatics, as compared to the control group [86]
To further demonstrate the importance of the lymphatic vasculature in IBD, vascular endothelial growth factor receptor-3 (VEGFR-3) blockade in IL-10 deficient mice led to a significant increase in disease severity with increased inflammation, impaired lymphatic function and morphology along with oedema in the colon [98]
Summary
The lymphatic system is an immense network responsible for maintaining tissue homeostasis through the transport of interstitial fluid, dietary lipids, macromolecules and immune cells [1]. A defective lymphatic system may lead to the accumulation of pro-inflammatory cells, signalling molecules and oedema, resulting in a feedback loop that fuels a state of chronic inflammation [5]. A storm of pro-inflammatory soluble mediators is produced and released that activate the innate immune response. The production and release of SPMs and anti-inflammatory cytokines halt PMN infiltration, while stimulating the recruitment and function of monocytes and pro-resolving macrophages [9]. Many chronic diseases are characterized by impaired resolution and a vicious cycle of continuous immune cell activation [14,15,16]. This review provides an overview of the abundance, and the effects of SPMs on the lymphatic system in relation to inflammatory diseases such as cardiovascular disease, acute respiratory distress syndrome, IBD and DED
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