The Interplay Between Lymphatic Vessels and Chemokines

Chemokines are a family of small protein cytokines that act as chemoattractants to migrating cells, in particular those of the immune system. They are categorized functionally as either homeostatic, constitutively produced by tissues for basal levels of cell migration, or inflammatory, where they are generated in association with a pathological inflammatory response. While the extravasation of leukocytes via blood vessels is a key step in cells entering the tissues, the lymphatic vessels also serve as a conduit for cells that are recruited and localized through chemoattractant gradients. Furthermore, the growth and remodeling of lymphatic vessels in pathologies is influenced by chemokines and their receptors expressed by lymphatic endothelial cells (LECs) in and around the pathological tissue. In this review we summarize the diverse role played by specific chemokines and their receptors in shaping the interaction of lymphatic vessels, immune cells, and other pathological cell types in physiology and disease

Radiation therapy attenuates lymphatic vessel repair by reducing VEGFR-3 signalling

Introduction: Surgery and radiotherapy are key cancer treatments and the leading causes of damage to the lymphatics, a vascular network critical to fluid homeostasis and immunity. The clinical manifestation of this damage constitutes a devastating side-effect of cancer treatment, known as lymphoedema. Lymphoedema is a chronic condition evolving from the accumulation of interstitial fluid due to impaired drainage via the lymphatics and is recognised to contribute significant morbidity to patients who survive their cancer. Nevertheless, the molecular mechanisms underlying the damage inflicted on lymphatic vessels, and particularly the lymphatic endothelial cells (LEC) that constitute them, by these treatment modalities, remain poorly understood.Methods: We used a combination of cell based assays, biochemistry and animal models of lymphatic injury to examine the molecular mechanisms behind LEC injury and the subsequent effects on lymphatic vessels, particularly the role of the VEGF-C/VEGF-D/VEGFR-3 lymphangiogenic signalling pathway, in lymphatic injury underpinning the development of lymphoedema.Results: We demonstrate that radiotherapy selectively impairs key LEC functions needed for new lymphatic vessel growth (lymphangiogenesis). This effect is mediated by attenuation of VEGFR-3 signalling and downstream signalling cascades. VEGFR-3 protein levels were downregulated in LEC that were exposed to radiation, and LEC were therefore selectively less responsive to VEGF-C and VEGF-D. These findings were validated in our animal models of radiation and surgical injury.Discussion: Our data provide mechanistic insight into injury sustained by LEC and lymphatics during surgical and radiotherapy cancer treatments and underscore the need for alternative non-VEGF-C/VEGFR-3-based therapies to treat lymphoedema

Intercostal Nerve Transfers to Native Triceps or Free Muscle Flaps for Elbow Extension in Brachial Plexus Injuries

Intercostal nerve donors for traumatic brachial plexus injury reconstruction have been used to neurotize native muscles or free-functioning muscle transfers, with inconsistent outcomes reported. The aim was to record a substantial series, evaluate functional outcomes, and identify prognostic factors. We present a single-surgeon case series of 21 consecutive patients who underwent 21 transfer procedures to either native muscles or free-functioning muscles to reconstruct elbow extension over a 9-year period. Outcome parameters included target muscle power grade and timing of recovery. A Medical Research Council power grade ≥ M4 was achieved in 17 reconstructions. The free-functioning muscle group had significantly higher success rate and reached their best power grade 14 months earlier. Free-functioning muscle reconstruction with intercostal nerve transfer is a more complex procedure but has quicker functional recovery and greater reliability in achieving grade M4