The Addition of Hyaluronidase to Tumescent Local Anesthesia Supports Lymphological Liposculpture of Secondary Lymphedema.
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ABSTRACT:
SUBMITTER: Cornely ME
PROVIDER: S-EPMC8769077 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Secondary lymphedema is a debilitating condition, and genetic factors predisposing to its development remain largely unknown. Adrenomedullin (AM) is peptide encoded, together with proadrenomedullin N-terminal peptide (PAMP), by the Adm gene (adrenomedullin gene). AM and its putative receptor calcitonin receptor-like receptor (CLR) are implicated in angiogenesis and lymphangiogenesis during embryogenesis and wound healing, suggesting their possible involvement in secondary lymphedema. To investigate whether AM deficiency predisposes to secondary lymphedema, we used heterozygous adult mice with Adm gene-knockin stop mutation, which selectively abrogated AM, but preserved PAMP, expression (Adm(AM+/?) animals). After hind limb skin incision, Adm messenger RNA expression was upregulated in wounded tissue of both Adm(AM+/+) and Adm(AM+/?) mice. However, only Adm(AM+/?) animals developed limb swelling and histopathological lymphedematous changes, including epidermal thickening, elevated collagen fiber density, and increased microvessel diameter. Secondary lymphedema was prevented when circulating AM levels in Adm(AM+/?) mice were restored by systemic peptide delivery. In human skin, CLR was expressed in tissue components affected by lymphedema, including epidermis, lymphatics, and blood vessels. Our study identified a previously unrecognized role for endogenous AM as a key factor in secondary lymphedema pathogenesis and provided experimental in vivo evidence of an underlying germ-line genetic predisposition to developing this disorder.
| S-EPMC3682392 | biostudies-literature
Project description:Acquired lymphedema is one of the most dreaded side effects of cancer treatment, such as surgical treatment or irradiation. However, due to the lack of appropriate animal models, there is no effective therapeutic method to cure acquired lymphedema. To develop a reproducible acquired lymphedema animal model, we devised a mouse hind limb model by removing a superficial inguinal lymph node, a popliteal lymph node, a deep inguinal lymph node, and the femoral lymphatic vessel. We measured the volume of lymphedematous leg and observed the change in level of hyaluronic acid (HA) and lymphangiogenic factors after injecting hyaluronidase. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that HA, a major component of extracellular matrix, accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating hyaluronidase. Following hyaluronidase injection, the lymphedematous region of our model resembled a normal hind limb. Our findings indicated that hyaluronidase promoted lymphangiogenesis on the lymphedematous limb. Based on hyaluronidase treatment in the lymphedematous region, this could potentially be a new therapeutic approach for acquired lymphedema mediated through the modification of the size of HA fragments. Impact statement In this manuscript, the essence of the work described in this manuscript involves the development of (1) a mouse limb model showing acquired lymphedema and (2) a potent therapeutic treatment using hyaluronidase to remedy acquired lymphedema in our model. In order to develop a reproducible acquired lymphedema animal model that reflects the most common symptoms experienced by lymphedema patients, we devised a mouse hind limb model by removing lymph nodes and lymphatics. Our model showed the distinguishable swelling and the reliable symptoms compared to previously reported models. In the lymphedematous regions of our model, we confirmed that hyaluronic acid (HA) accumulated to higher levels than in a normal mouse. This lymphedema volume was rapidly reduced by treating the lymphedematous leg with hyaluronidase, which also degraded high molecular weight HA to low molecular weight HA. Immunohistochemical analysis, quantitative real-time PCR analysis and lymphangioscintigraphy showed that hyaluronidase enhanced lymphangiogenesis in the lymphedematous limb.
| S-EPMC5685261 | biostudies-literature
Project description:An injectable local anesthetic producing repeatable on-demand nerve block would be desirable for pain management. Here we present a phototriggerable device to achieve repeatable and adjustable on-demand local anesthesia in superficial or deep tissues, consisting of gold nanorods attached to low temperature sensitive liposomes (LTSL). The particles were loaded with tetrodotoxin and dexmedetomidine. Near-infrared light (NIR, 808 nm, continuous wave) could heat gold nanorods at low fluence (short duration and low irradiance), leading to rapid release of payload. In vivo, 1-2 min of irradiation at ?272 mW/cm2 produced repeatable and adjustable on-demand infiltration anesthesia or sciatic nerve blockade with minimal toxicity. The nerve block intensity and duration correlated with the irradiance and duration of the applied light.
| S-EPMC5469101 | biostudies-literature
Project description:Several conservative (i.e., nonpharmacologic, nonsurgical) treatments exist for secondary lymphedema. The optimal treatment is unknown. We examined the effectiveness of conservative treatments for secondary lymphedema, as well as harms related to these treatments.We searched MEDLINE®, EMBASE®, Cochrane Central Register of Controlled Trials®, AMED, and CINAHL from 1990 to January 19, 2010. We obtained English- and non-English-language randomized controlled trials or observational studies (with comparison groups) that reported primary effectiveness data on conservative treatments for secondary lymphedema. For English-language studies, we extracted data in tabular form and summarized the tables descriptively. For non-English-language studies, we summarized the results descriptively and discussed similarities with the English-language studies.Thirty-six English-language and eight non-English-language studies were included in the review. Most of these studies involved upper-limb lymphedema secondary to breast cancer. Despite lymphedema's chronicity, lengths of follow-up in most studies were under 6 months. Many trial reports contained inadequate descriptions of randomization, blinding, and methods to assess harms. Most observational studies did not control for confounding. Many studies showed that active treatments reduced the size of lymphatic limbs, although extensive between-study heterogeneity in areas such as treatment comparisons and protocols, and outcome measures, prevented us from assessing whether any one treatment was superior. This heterogeneity also precluded us from statistically pooling results. Harms were rare (< 1% incidence) and mostly minor (e.g., headache, arm pain).The literature contains no evidence to suggest the most effective treatment for secondary lymphedema. Harms are few and unlikely to cause major clinical problems.
| S-EPMC3320521 | biostudies-literature
Project description:Secondary lymphedema, a life-long complication of cancer treatment, currently has no cure. Lymphedema patients have decreased quality of life and recurrent infections with treatments limited to palliative measures. Accumulating evidence indicates that T cells play a key role in the pathology of lymphedema by promoting tissue fibrosis and inhibiting lymphangiogenesis. Here using mouse models, we show that topical therapy with tacrolimus, an anti-T-cell immunosuppressive drug, is highly effective in preventing lymphedema development and treating established lymphedema. This intervention markedly decreases swelling, T-cell infiltration and tissue fibrosis while significantly increasing formation of lymphatic collaterals with minimal systemic absorption. Animals treated with tacrolimus have markedly improved lymphatic function with increased collecting vessel contraction frequency and decreased dermal backflow. These results have profound implications for lymphedema treatment as topical tacrolimus is FDA-approved for other chronic skin conditions and has an established record of safety and tolerability.
| S-EPMC5309859 | biostudies-other
Project description:Patients who suffer from lymphedema have impaired immunity and, as a result, are at an increased risk for infections. Furthermore, previous studies have shown that lymphadenectomy impairs acquisition of adaptive immune responses and antibody production in response to foreign antigens. Although it is clear that antigen presentation in lymph nodes plays a key role in adaptive immunity, the cellular mechanisms that regulate impaired immune responses in patients with lymphedema or following lymphatic injury remain unknown. We have previously found that axillary lymph node dissection, both clinically and in a mouse model, results in a marked increase in the number of regulatory T cells in the ipsilateral limb. In this study, we focus on the role of regulatory T cells in immunosuppression and show that regulatory T-cell proliferation in tissues distal to site of lymphatic injury contributes to impaired innate and adaptive immune responses. More importantly, using Foxp3-DTR transgenic mice, we show that depletion of regulatory T cells in the setting of lymphatic injury restores these critical immune-mediated responses. These findings provide additional evidence that immune responses following lymphatic injury play a key role in mediating the pathology of lymphedema.
| S-EPMC5794510 | biostudies-literature
Project description:In this study we evaluated the role of hyaluronan (HA) in reactive adipogenesis, a local expansion of preadipocytes that provides host defense by release of antimicrobial peptides. We observed that HA accumulated during maturation of adipocytes in vitro and was associated with increased expression of preadipocyte factor 1 (Pref-1), Zinc finger protein 423 (Zfp423) and early B cell factor 1 (Ebf1). Although HA is normally abundant in the extracellular matrix, a further increase in HA staining occurred in mice at sites of reactive adipogenesis following injury of colon by dextran sodium sulfate or injury of skin from infection with S. aureus. HA also abundantly accumulated around adipocytes seen in the colon of patients with inflammatory bowel disease. This HA was necessary for adipocyte maturation since digestion of HA by administration of soluble hyaluronidase or transgenic expression of hyaluronidase 1 inhibited adipogenesis in vitro and in vivo. Furthermore, hyaluronidase also suppressed inflammation of both skin and colon and decreased antimicrobial peptide expression by developing preadipocytes. This resulted in increased bacterial transit across the epithelial barrier despite decreased tissue injury from inflammation. These observations suggest HA plays an important role in reactive adipogenesis and host defense after injury.
2018-09-13 | GSE119826 | GEO
Project description:BackgroundConscious sedation is regularly used in ambulatory surgery to improve patient outcomes, in particular patient satisfaction. Reports suggest that the addition of conscious sedation to local anesthesia for inguinal hernioplasty is safe and effective in improving patient satisfaction. No previous randomized controlled trial has assessed the benefit of conscious sedation in this regard.ObjectiveTo determine whether the addition of conscious sedation to local anesthesia improves patient satisfaction with inguinal hernioplasty.MethodsThis trial is designed as a single-center, randomized, placebo-controlled, blinded trial of 148 patients. Adult patients diagnosed with a reducible, unilateral inguinal hernia eligible for hernioplasty using local anesthesia will be recruited. The intervention will be the use of intravenous midazolam for conscious sedation. Normal saline will be used as placebo in the control group. The primary outcome will be patient satisfaction, measured using the validated Iowa Satisfaction with Anesthesia Scale. Secondary outcomes will include intra- and postoperative pain, operative time, volumes of sedative agent and local anesthetic used, time to discharge, early and late complications, and postoperative functional status.ResultsTo date, 171 patients have been recruited. Surgery has been performed on 149 patients, meeting the sample size requirements. Follow-up assessments are still ongoing. Trial completion is expected in August 2017.ConclusionsThis randomized controlled trial is the first to assess the effectiveness of conscious sedation in improving patient satisfaction with inguinal hernioplasty using local anesthesia. If the results demonstrate improved patient satisfaction with conscious sedation, this would support routine incorporation of conscious sedation in local inguinal hernioplasty and potentially influence national and international hernia surgery guidelines.Trial registrationClinicaltrials.gov NCT02444260; https://clinicaltrials.gov/ct2/show/NCT02444260 (Archived by WebCite at http://www.webcitation.org/6no8Dprp4).
| S-EPMC5320391 | biostudies-literature
Project description:Lymphedema is the abnormal accumulation of protein-rich fluid in the interstitial space. Primary lymphedema is a rare genetic condition with both autosomal dominant and autosomal recessive modes of inheritance. Three genes, FLT4 (VEGFR3), FOXC2, and SOX18 cause varying forms of primary lymphedema. In industrialized countries, secondary lymphedema is usually associated with cancer therapy and/or trauma. Recent observations suggested that hepatocyte growth factor/high affinity hepatocyte growth factor receptor (HGF/MET) were new candidate lymphedema genes.The coding exons and flanking regions of HGF and MET were directly sequenced in 145 lymphedema probands, 59 unrelated women with secondary lymphedema following treatment for breast cancer, 21 individual patients with lymphedema and intestinal lymphangiectasia, and at least 159 unrelated ethnic matched control individuals. Mutations leading to truncation or missense changes in evolutionarily conserved residues of HGF and MET were identified. These mutations were not polymorphic in control individuals.The identification of HGF/MET mutations in primary lymphedema, lymphedema/lymphangiectasia, and breast cancer-associated secondary lymphedema suggests that the HGF/MET pathway is causal or alters susceptibility for a broad range of lymphedema phenotypes. The HGF/MET pathway provides a new target for the prevention and/or treatment of lymphedema.
| S-EPMC4298750 | biostudies-literature