Lymphatic endothelium in health and disease

The lymphatic vascular system has an important role in the maintenance of tissue fluid pressure homeostasis, in the mediation of the afferent immune response via recruitment of antigen-presenting cells toward draining lymph nodes, and in the intestinal absorption of dietary lipids. Substantial progress in our understanding of the development and the molecular mechanisms controlling the lymphatic system has been made during the last few years, based on a recent wave of discoveries of lymphatic endothelial cell-specific markers and growth factors. This has also led to new insights into the role of lymphatic endothelium in a number of diseases, including primary and secondary lymphedemas. The emerging role of lymphatic endothelium in the context of inflammation indicates that therapeutics targeting the lymphatic vasculature might represent a new strategy for anti-inflammatory therapie

Multidisciplinary Consideration of Potential Pathophysiologic Mechanisms of Paradoxical Erythema with Topical Brimonidine Therapy.

Rosacea is a chronic inflammatory disease with transient and non-transient redness as key characteristics. Brimonidine is a selective α2-adrenergic receptor (AR) agonist approved for persistent facial erythema of rosacea based on significant efficacy and good safety data. The majority of patients treated with brimonidine report a benefit; however, there have been sporadic reports of worsening erythema after the initial response. A group of dermatologists, receptor physiology, and neuroimmunology scientists met to explore potential mechanisms contributing to side effects as well as differences in efficacy. We propose the following could contribute to erythema after application: (1) local inflammation and perivascular inflammatory cells with abnormally functioning ARs may lead to vasodilatation; (2) abnormal saturation and cells expressing different AR subtypes with varying ligand affinity; (3) barrier dysfunction and increased skin concentrations of brimonidine with increased actions at endothelial and presynaptic receptors, resulting in increased vasodilation; and (4) genetic predisposition and receptor polymorphism(s) leading to different smooth muscle responses. Approximately 80% of patients treated with brimonidine experience a significant improvement without erythema worsening as an adverse event. Attention to optimizing skin barrier function, setting patient expectations, and strategies to minimize potential problems may possibly reduce further the number of patients who experience side effects.FundingGalderma International S.A.S., Paris, France

T Cell Migration from Inflamed Skin to Draining Lymph Nodes Requires Intralymphatic Crawling Supported by ICAM-1/LFA-1 Interactions.

T cells are the most abundant cell type found in afferent lymph, but their migration through lymphatic vessels (LVs) remains poorly understood. Performing intravital microscopy in the murine skin, we imaged T cell migration through afferent LVs in vivo. T cells entered into and actively migrated within lymphatic capillaries but were passively transported in contractile collecting vessels. Intralymphatic T cell number and motility were increased during contact-hypersensitivity-induced inflammation and dependent on ICAM-1/LFA-1 interactions. In vitro, blockade of endothelial cell-expressed ICAM-1 reduced T cell adhesion, crawling, and transmigration across lymphatic endothelium and decreased T cell advancement from capillaries into lymphatic collectors in skin explants. In vivo, T cell migration to draining lymph nodes was significantly reduced upon ICAM-1 or LFA-1 blockade. Our findings indicate that T cell migration through LVs occurs in distinct steps and reveal a key role for ICAM-1/LFA-1 interactions in this process

Dynamics of lymphatic regeneration and flow patterns after lymph node dissection

Knowledge about the mechanisms of regeneration of the lymphatic vasculature after surgical trauma is essential for the development of strategies for the prevention and therapy of lymphedema. However, little is known about the alterations of lymphatic flow directly after surgical trauma. We investigated lymphatic function in mice using near-infrared imaging for a period of 4weeks after surgeries that mimic sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND), by removal of the popliteal lymph node (LN) alone or together with the popliteal fat pad, respectively. SLNB-like surgery did not cause changes in lymphatic drainage in the majority of cases. In contrast, lymphatic drainage impairment shown by collecting vessel rupture, dermal backflow and rerouting of lymph flow via collateral vessels were observed after ALND-like surgery. All collateral vessels drained to the inguinal LN. These results indicate that less invasive surgery prevents lymphatic decompensation. They also reveal the development and maturation of collateral lymphatic vessels after extensive surgical trauma, which reroute the flow of lymph towards a different LN. These findings might be helpful for the development of strategies to prevent and/or treat post-surgical lymphedem

Non-invasive dynamic near-infrared imaging and quantification of vascular leakage in vivo

Preclinical vascular research has been hindered by a lack of methods that can sensitively image and quantify vascular perfusion and leakage in vivo. In this study, we have developed dynamic near-infrared imaging methods to repeatedly visualize and quantify vascular leakage in mouse skin in vivo, and we have applied these methods to transgenic mice with overexpression of vascular endothelial growth factors VEGF-A or -C. Near-infrared dye conjugates were developed to identify a suitable vascular tracer that had a prolonged circulation lifetime and slow leakage into normal tissue after intravenous injection. Dynamic simultaneous imaging of ear skin and a large blood vessel in the leg enabled determination of the intravascular signal (blood volume fraction) from the tissue signal shortly after injection and quantifications of vascular leakage into the extravascular tissue over time. This method allowed for the sensitive detection of increased blood vascularity and leakage rates in K14-VEGF-A transgenic mice and also reliably measured inflammation-induced changes of vascularity and leakage over time in the same mice. Measurements after injection of recombinant VEGF-A surprisingly revealed increased blood vascular leakage and lymphatic clearance in K14-VEGF-C transgenic mice which have an expanded cutaneous lymphatic vessel network, potentially indicating unanticipated effects of lymphatic drainage on vascular leakage. Increased vascular leakage was also detected in subcutaneous tumors, confirming that the method can also be applied to deeper tissues. This new imaging method might facilitate longitudinal investigations of the in vivo effects of drug candidates, including angiogenesis inhibitors, in preclinical disease model

Алгоритм ведения больных с гнойными тубовариальными образованиями

ТАЗОВЫХ ОРГАНОВ ВОСПАЛИТЕЛЬНЫЕ БОЛЕЗНИАЛГОРИТМЫНАГНОЕНИЕБОЛЬНОГО ВЕДЕНИЕ ОПТИМАЛЬНО

Inflammation and Lymphatic Function

The lymphatic vasculature plays a crucial role in regulating the inflammatory response by influencing drainage of extravasated fluid, inflammatory mediators, and leukocytes. Lymphatic vessels undergo pronounced enlargement in inflamed tissue and display increased leakiness, indicating reduced functionality. Interfering with lymphatic expansion by blocking the vascular endothelial growth factor C (VEGF-C)/vascular endothelial growth factor receptor 3 (VEGFR-3) signaling axis exacerbates inflammation in a variety of disease models, including inflammatory bowel disease (IBD), rheumatoid arthritis and skin inflammation. In contrast, stimulation of the lymphatic vasculature, e.g., by transgenic or viral overexpression as well as local injections of VEGF-C, has been shown to reduce inflammation severity in models of rheumatoid arthritis, skin inflammation, and IBD. Strikingly, the induced expansion of the lymphatic vasculature improves lymphatic function as assessed by the drainage of dyes, fluorescent tracers or inflammatory cells and labeled antigens. The drainage performance of lymphatic vessels is influenced by vascular permeability and pumping activity, which are influenced by VEGF-C/VEGFR-3 signaling as well as several inflammatory mediators, including TNF-α, IL-1β, and nitric oxide. Considering the beneficial effects of lymphatic activation in inflammation, administration of pro-lymphangiogenic factors like VEGF-C, preferably in a targeted, inflammation site-specific fashion, represents a promising therapeutic approach in the setting of inflammatory pathologies

Lymphatic vessels: new targets for the treatment of inflammatory diseases

The lymphatic system plays an important role in the physiological control of the tissue fluid balance and in the initiation of immune responses. Recent studies have shown that lymphangiogenesis, the growth of new lymphatic vessels and/or the expansion of existing lymphatic vessels, is a characteristic feature of acute inflammatory reactions and of chronic inflammatory diseases. In these conditions, lymphatic vessel expansion occurs at the tissue level but also within the draining lymph nodes. Surprisingly, activation of lymphatic vessel function by delivery of vascular endothelial growth factor-C exerts anti-inflammatory effects in several models of cutaneous and joint inflammation. These effects are likely mediated by enhanced drainage of extravasated fluid and inflammatory cells, but also by lymphatic vessel-mediated modulation of immune responses. Although some of the underlying mechanisms are just beginning to be identified, lymphatic vessels have emerged as important targets for the development of new therapeutic strategies to treat inflammatory conditions. In this context, it is of great interest that some of the currently used anti-inflammatory drugs also potently activate lymphatic vessels

Dynamics of lymphatic regeneration and flow patterns after lymph node dissection.

Knowledge about the mechanisms of regeneration of the lymphatic vasculature after surgical trauma is essential for the development of strategies for the prevention and therapy of lymphedema. However, little is known about the alterations of lymphatic flow directly after surgical trauma. We investigated lymphatic function in mice using near-infrared imaging for a period of 4 weeks after surgeries that mimic sentinel lymph node biopsy (SLNB) or axillary lymph node dissection (ALND), by removal of the popliteal lymph node (LN) alone or together with the popliteal fat pad, respectively. SLNB-like surgery did not cause changes in lymphatic drainage in the majority of cases. In contrast, lymphatic drainage impairment shown by collecting vessel rupture, dermal backflow and rerouting of lymph flow via collateral vessels were observed after ALND-like surgery. All collateral vessels drained to the inguinal LN. These results indicate that less invasive surgery prevents lymphatic decompensation. They also reveal the development and maturation of collateral lymphatic vessels after extensive surgical trauma, which reroute the flow of lymph towards a different LN. These findings might be helpful for the development of strategies to prevent and/or treat post-surgical lymphedema