New Insights into the Pathophysiology of Primary and Secondary Lymphedema: Histopathological Studies on Human Lymphatic Collecting Vessels

Barone, Virginia; Borghini, Annalisa; Clemente, Erica Tedone; Aglianò, Margherita; Gabriele, Guido; Gennaro, Paolo; Weber, Elisabetta

doi:10.1089/lrb.2020.0037

Cited by 19 publications

(23 citation statements)

References 23 publications

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“…The diameters of the lymphatic collectors in the postoperative PAL images were also significantly wider than those in preoperative PAL images in cases 1 and 2. In lymphedema, lymphatic vessels are initially dilated owing to increased lymphatic pressure, but they become contracted due to wall thickening as lymphedema progresses [13]. A change in the diameter of a lymphatic vessel can reflect disease progression according to the above-described pathophysiology of lymphedema.…”

Section: Discussionmentioning

confidence: 99%

Photoacoustic lymphangiography before and after lymphaticovenular anastomosis

Kajita

Matoba

et al. 2021

Arch Plast Surg

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Background Lymphaticovenular anastomosis (LVA) is a minimally invasive surgical procedure used to treat lymphedema. Volumetric measurements and quality-of-life assessments are often performed to assess the effectiveness of LVA, but there is no method that provides information regarding postoperative morphological changes in lymphatic vessels and veins after LVA. Photoacoustic lymphangiography (PAL) is an optical imaging technique that visualizes the distribution of light-absorbing molecules, such as hemoglobin or indocyanine green (ICG), and provides three-dimensional images of superficial lymphatic vessels and the venous system simultaneously. In this study, we performed PAL in lymphedema patients before and after LVA and compared the images to evaluate the effect of LVA.Methods PAL was performed using the PAI-05 system in three patients (one man, two women) with lymphedema, including one primary case and two secondary cases, before LVA. ICG fluorescence lymphography was performed in all cases before PAL. Follow-up PAL was performed between 5 days and 5 months after LVA.Results PAL enabled the simultaneous visualization of clear lymphatic vessels that could not be accurately seen with ICG fluorescence lymphography and veins. We were also able to observe and analyze morphological changes such as the width and the number of lymphatic vessels and veins during the follow-up PAL after LVA.Conclusions By comparing preoperative and postoperative PAL images, it was possible to analyze the morphological changes in lymphatic vessels and veins that occurred after LVA. Our study suggests that PAL would be useful when assessing the effect of LVA surgery.

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Section: Discussionmentioning

confidence: 99%

Photoacoustic lymphangiography before and after lymphaticovenular anastomosis

Kajita

Matoba

et al. 2021

Arch Plast Surg

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Section: Hypothesis Summary (Interstitial Inflammatory Stasis)mentioning

confidence: 99%

“…These vessels were found to have occluded lumens causing impairment of the normal lymphatic-pump mechanism. Most significantly, many of the contractile cells responsible for impairing lymphatic drainage were identified as myofibroblasts , not vascular smooth muscle cells, and were characterized by increased ECM synthesis ( 126 ). Also in support of the IIS hypothesis is a finding of Asano et al who demonstrated increased levels of inflammatory cytokines, namely TNF-a and IL-1b, in the walls of dysfunctional lymphatic collecting vessels ( 127 ).…”

Section: Interstitial Inflammatory Stasis Hypothesismentioning

confidence: 99%

Impaired Lymphatic Drainage and Interstitial Inflammatory Stasis in Chronic Musculoskeletal and Idiopathic Pain Syndromes: Exploring a Novel Mechanism

et al. 2021

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A normal functioning lymphatic pump mechanism and unimpaired venous drainage are required for the body to remove inflammatory mediators from the extracellular compartment. Impaired vascular perfusion and/or lymphatic drainage may result in the accumulation of inflammatory substances in the interstitium, creating continuous nociceptor activation and related pathophysiological states including central sensitization and neuroinflammation. We hypothesize that following trauma and/or immune responses, inflammatory mediators may become entrapped in the recently discovered interstitial, pre-lymphatic pathways and/or initial lymphatic vessels. The ensuing interstitial inflammatory stasis is a pathophysiological state, created by specific pro-inflammatory cytokine secretion including tumor necrosis factor alpha, interleukin 6, and interleukin 1b. These cytokines can disable the local lymphatic pump mechanism, impair vascular perfusion via sympathetic activation and, following transforming growth factor beta 1 expression, may lead to additional stasis through direct fascial compression of pre-lymphatic pathways. These mechanisms, when combined with other known pathophysiological processes, enable us to describe a persistent feed-forward loop capable of creating and maintaining chronic pain syndromes. The potential for concomitant visceral and/or vascular dysfunction, initiated and maintained by the same feed-forward inflammatory mechanism, is also described.

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“…Lymphoedema is classified into primary lymphoedema, which is an inherited or congenital condition resulting from malformation of the lymphatic system, while secondary lymphoedema is more common and results from injury or damage to the lymphatic system. The initial stages of lymphoedema are not completely understood, although ultrasonography, histology and microscopy studies have elucidated the physiological and structural changes of collecting vessels during the onset of lymphoedema [5,6]. Initially, in secondary lymphoedema, the collecting lymphatic vessels transition from the normal to the ectasis type, a dilated vessel with a greatly enlarged lumen.…”

Section: Introductionmentioning

confidence: 99%

“…Finally, there is progression to the sclerosis type with a narrowed vessel lumen, the loss of elasticity and lymphatic contractility. In primary lymphoedema, the ectasis and sclerosis types have been observed, while the contraction type has not been observed [5].…”

Section: Introductionmentioning

confidence: 99%

Lymphoedema conditions disrupt endothelial barrier function in vitro

Hall

Farzaneh

Galangashi

et al. 2022

J. R. Soc. Interface.

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Lymphatic vessel contractions generate net antegrade pulsatile lymph flow. By contrast, impaired lymphatic vessels are often associated with lymphoedema and altered lymph flow. The effect of lymphoedema on the lymph flow field and endothelium is not completely known. Here, we characterized the lymphatic flow field of a platelet-specific receptor C-type lectin-like receptor 2 (CLEC2) deficient lymphoedema mouse model. In regions of lymphoedema, collecting vessels were significantly distended, vessel contractility was greatly diminished and pulsatile lymph flow was replaced by quasi-steady flow. In vitro exposure of human dermal lymphatic endothelial cells (LECs) to lymphoedema-like quasi-steady flow conditions increased intercellular gap formation and permeability in comparison to normal pulsatile lymph flow. In the absence of flow, LECs exposed to steady pressure (SP) increased intercellular gap formation in contrast with pulsatile pressure (PP). The absence of pulsatility in steady fluid flow and SP conditions without flow-induced upregulation of myosin light chain (MLCs) regulatory subunits 9 and 12B mRNA expression and phosphorylation of MLCs, in contrast with pulsatile flow and PP without flow. These studies reveal that the loss of pulsatility, which can occur with lymphoedema, causes LEC contraction and an increase in intercellular gap formation mediated by MLC phosphorylation.

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New Insights into the Pathophysiology of Primary and Secondary Lymphedema: Histopathological Studies on Human Lymphatic Collecting Vessels

Cited by 19 publications

References 23 publications

Photoacoustic lymphangiography before and after lymphaticovenular anastomosis

Photoacoustic lymphangiography before and after lymphaticovenular anastomosis

Impaired Lymphatic Drainage and Interstitial Inflammatory Stasis in Chronic Musculoskeletal and Idiopathic Pain Syndromes: Exploring a Novel Mechanism

Lymphoedema conditions disrupt endothelial barrier function in vitro

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