The lymphatic system—the body’s forgotten sewer system that nobody takes care of?

Aim of the study: Mammals have two specialized vascular circulatory systems: the blood vasculature and the lymphatic vasculature. The lymphatic vasculature is a unidirectional conduit that returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation.

Results: It also plays major roles in immune cell trafficking and lipid absorption. As we discuss in this review, the molecular characterization of lymphatic vascular development and our understanding of this vasculature's role in pathophysiological conditions has greatly improved in recent years, changing conventional views about the roles of the lymphatic vasculature in health and disease. Morphological or functional defects in the lymphatic vasculature have now been uncovered in several pathological conditions. We propose that subtle asymptomatic alterations in lymphatic vascular function could underlie the variability seen in the body's response to a wide range of human diseases.

Aim of the study: Lymphatic vessels have an active role in draining excess interstitial fluid from organs and serving as conduits for immune cell trafficking to lymph nodes. In the central circulation, the force needed to propel blood forward is generated by the heart.

Results: In contrast, lymphatic vessels rely on intrinsic vessel contractions in combination with extrinsic forces for lymph propulsion. The intrinsic pumping features phasic contractions generated by lymphatic smooth muscle. Periodic, bicuspid valves composed of endothelial cells prevent backflow of lymph. This work provides a brief overview of lymph transport, including initial lymph formation along with cellular and molecular mechanisms controlling lymphatic vessel pumping.

Aim of the study: The glymphatic system and meningeal lymphatics have recently been characterized. Glymphatic system is a glia-dependent system of perivascular channels, and it plays an important role in the removal of interstitial metabolic waste products.

Results: Breakdowns and dysfunction of the glymphatic system and meningeal lymphatics play a crucial role in age-related brain changes, the pathogenesis of neurovascular and neurodegenerative diseases, as well as in brain injuries and tumors. This review discusses the relationship recently characterized meningeal lymphatic vessels with the glymphatic system, which provides perfusion of the CNS with cerebrospinal and interstitial fluids. The review also presents the results of human studies concerning both the presence of meningeal lymphatics and the glymphatic system. A new understanding of how aging, medications, sleep and wake cycles, genetic predisposition, and even body posture affect the brain drainage system has not only changed the idea of brain fluid circulation but has also contributed to an understanding of the pathology and mechanisms of neurodegenerative diseases.

Aim of the study: Background Lymphedema is an accumulation of protein-rich fluid in the interstitial spaces resulting from impairment in the lymphatic circulation that can impair quality of life and cause considerable morbidity. Lower extremity lymphedema (LEL) has an overall incidence rate of 20%.

Results: All, except one study, reported positive outcomes based on limb circumference and volume changes or subjective clinical improvement. The largest reduction rate in limb circumference and volume was 63.8%. Conclusion LVA demonstrated a considerable reduction in limb volume and improvement in subjective findings of lymphedema in the majority of patients. The maintained effectiveness of this treatment modality in long-term follow-up suggests great efficacy of LVA in LEL treatment.

Aim of the study: Although the sympathetic nerve system has been described as a modulator of lymphatic circulation, it has not been targeted in the treatment of lymphedema. We conducted a systematic review of publications assessing the use of sympathetic nerve block in lymphedema treatment.

Results: All papers identified were clinical, reporting on a total of 187 patients. Sympathetic nerve block was proposed with local anesthetics, whether or not associated with triamcinolone. Treatment with a nerve block promoted lymphedema improvement expressed by decreased limb circumference and patient-reported outcomes. Large randomized clinical trials are still pending, but sympathetic nerve block seems to be a promising alternative for lymphedema patients who do not respond to conservative therapy.

Aim of the study: Cerebral oedema is associated with morbidity and mortality after traumatic brain injury (TBI)1. Noradrenaline levels are increased after TBI2-4, and the amplitude of the increase in noradrenaline predicts both the extent of injury5 and the likelihood of mortality6.

Results: This post-TBI adrenergic storm was associated with reduced contractility of cervical lymphatic vessels, consistent with diminished return of glymphatic and lymphatic fluid to the systemic circulation. Accordingly, pan-adrenergic receptor inhibition normalized central venous pressure and partly restored glymphatic and cervical lymphatic flow in a mouse model of TBI, and these actions led to substantially reduced brain oedema and improved functional outcomes. Furthermore, post-traumatic inhibition of adrenergic signalling boosted lymphatic export of cellular debris from the traumatic lesion, substantially reducing secondary inflammation and accumulation of phosphorylated tau. These observations suggest that targeting the noradrenergic control of central glymphatic flow may offer a therapeutic approach for treating acute TBI.

Aim of the study: Skull development coincides with the onset of cerebrospinal fluid (CSF) circulation, brain-CSF perfusion, and meningeal lymphangiogenesis, processes essential for brain waste clearance. How these processes are affected by craniofacial disorders such as craniosynostosis are poorly understood.

Results: Treating craniosynostosis mice with Yoda1, a small molecule agonist for Piezo1, reduces intracranial pressure and improves CSF flow, in addition to restoring meningeal lymphangiogenesis, drainage to the deep cervical lymph nodes, and brain-CSF perfusion. Leveraging these findings, we show that Yoda1 treatments in aged mice with reduced CSF flow and turnover improve lymphatic networks, drainage, and brain-CSF perfusion. Our results suggest that CSF provides mechanical force to facilitate meningeal lymphatic growth and maintenance. Additionally, applying Yoda1 agonist in conditions with raised intracranial pressure and/or diminished CSF flow, as seen in craniosynostosis or with ageing, is a possible therapeutic option to help restore meningeal lymphatic networks and brain-CSF perfusion.

Aim of the study: Alzheimer's Disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive decline. Its characteristic pathological features include Aβ plaque deposition and abnormal tau protein aggregation. Biomarker testing has improved AD diagnosis. However, current treatments are primarily symptomatic, and no effective therapies are available to slow disease progression.

Results: The proposal of the glymphatic system has refined the theory of cerebral fluid circulation and waste clearance. Its dysfunction is closely associated with neurodegenerative diseases such as Alzheimer's Disease (AD) and Parkinson's Disease (PD), providing a novel target for AD treatment. Deep cervical Lymphatic-Venous Anastomosis (LVA), as an emerging surgical approach with potential to alleviate AD symptoms, has been initially validated for its short-term efficacy. However, it is still in the early stage of clinical exploration, and further systematic research is required for its successful clinical translation. Breakthroughs in the central lymphatic system have provided an important direction for exploring the pathological mechanisms of AD and developing innovative therapeutic strategies.