Impacts of arterial ischemia or venous occlusion on vascularized groin lymph nodes in a rat model

Tinhofer, Ines; Yang, Chan-Shan; Chen, Courtney; Cheng, Ming‐Huei

doi:10.1002/jso.25518

Cited by 14 publications

(18 citation statements)

References 32 publications

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“…Moreover, lymph nodes undergoing 120 minutes ischemia also contained markedly higher numbers of proliferating PCNA + and apoptotic Casp-3 + cells as well as CD68 + macrophages and MPO + neutrophilic granulocytes when compared to lymph nodes of the IR-45 and control group. In contrast to our findings, the current opinion on critical ischemia time of VLN flaps is four hours as evaluated for inguinal VLN flaps in a rat model [28,29]. However, a recent analysis of inflammatory biomarkers revealed that significant IR injury can occur with as little as two hours of ischemia [30].…”

Section: Plos Onecontrasting

confidence: 99%

Short-term molecular and cellular effects of ischemia/reperfusion on vascularized lymph node flaps in rats

et al. 2020

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Vascularized lymph node (VLN) transfer is an emerging strategy to re-establish lymphatic drainage in chronic lymphedema. However, the biological processes underlying lymph node integration remain elusive. This study introduces an experimental approach facilitating the analysis of short-term molecular and cellular effects of ischemia/reperfusion on VLN flaps. Lymph node flaps were dissected pedicled on the lateral thoracic vessels in 44 Lewis rats. VLN flaps were exposed to 45 or 120 minutes ischemia by in situ clamping of the vascular pedicle with subsequent reperfusion for 24 hours. Flaps not exposed to ischemia/reperfusion served as controls. Lymph nodes and the perinodal adipose tissue were separately analyzed by Western blot for the expression of lymphangiogenic and angiogenic growth factors. Moreover, morphology, microvessel density, proliferation, apoptosis and immune cell infiltration of VLN flaps were further assessed by histology and immunohistochemistry. Ischemia for 120 minutes was associated with a markedly reduced cellularity of lymph nodes but not of the perinodal adipose tissue. In line with this, ischemic lymph nodes exhibited a significantly lower microvessel density and an increased expression of VEGF-D and VEGF-A. However, VEGF-C expression was not upregulated. In contrast, analyses of the perinodal adipose tissue revealed a more subtle decrease of microvessel density, while only the expression of VEGF-D was increased. Moreover, after 120 minutes ischemia, lymph nodes but not the perinodal adipose tissue exhibited significantly higher numbers of proliferating and apoptotic cells as well as infiltrated macrophages and neutrophilic granulocytes compared with non-ischemic flaps. Taken together, lymph nodes of VLN flaps are highly susceptible to ischemia/reperfusion injury. In contrast, the perinodal adipose tissue is less prone to ischemia/reperfusion injury.

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Section: Plos Onecontrasting

confidence: 99%

Short-term molecular and cellular effects of ischemia/reperfusion on vascularized lymph node flaps in rats

et al. 2020

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“…However, a few mixed results were reported [ 18 , 19 ], including a case report with exacerbated lymphedema after VLNT [ 26 ]. Possible causes of suboptimal post-VLNT results include poor lymphangiogenesis and neo-lymphangiogenesis [ 2 , 27 ]; the quantity of LNs in the LN flap, which was shown to possess direct correlations with lymphatic drainage in animal models [ 28 ]; ischemic reperfusion injury during VLNT [ 29 , 30 , 31 ]; and pedicle complications (arterial or venous occlusion) during or after VLNT [ 30 ].…”

Section: Discussionmentioning

confidence: 99%

Lower Limb Lymphedema Patients Can Still Benefit from Supermicrosurgical Lymphaticovenous Anastomosis (LVA) after Vascularized Lymph Node Flap Transfer (VLNT) as Delayed Lymphatic Reconstruction—A Retrospective Cohort Study

Yang

Hayashi

et al. 2021

JCM

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Background: For lymphedema patients who received a vascularized lymph node flap transfer (VLNT) as their primary treatment, what are the treatment options when they seek further improvement? With recent publications supporting the use of lymphaticovenous anastomosis (LVA) for treating severe lymphedema, we examined whether LVA could benefit post-VLNT patients seeking further improvement. Methods: This retrospective cohort study enrolled eight lymphedema patients with nine lymphedematous limbs (one patient suffered from bilateral lower limb lymphedema) who had received VLNT as their primary surgery. Patients with previous LVA, liposuction, excisional therapy, or incomplete data were excluded. LVA was performed on nine lower lymphedematous limbs. Demographic data and intraoperative findings were recorded. Preoperative and postoperative limb volumes were measured with magnetic resonance volumetry. The primary outcome was the limb volume measured 6 months post-LVA. Results: The median duration of lymphedema before LVA was 10.5 (4.9–15.3) years. The median waiting time between VLNT and LVA was 41.4 (22.3–97.9) months. The median volume gained in the lymphedematous limb was 3836 (2505–4584) milliliters (mL). The median post-LVA follow-up period was 18 (6–30) months. Significant 6-month and 1-year post-LVA percentage volume reductions were found compared to pre-LVA volume (both p < 0.001). Conclusion: Based on the results from this study, the authors recommend the use of LVA as a secondary procedure for post-VLNT patients seeking further improvement.

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“…Critical ischemia time in muscle, skin, and other tissues have been extensively investigated in animal and human models [15,[18][19][20]. Relatively little is known about the effect of ischemia and ischemia-reperfusion injury on lymph nodes and lymphatic tissue [21,22]. Since we recently developed and characterized a transgenic rat which facilitates in situ real time visualization of lymphatic tissue (Prox1-EGFP), this has enabled us to precisely identify and isolate lymph nodes from surrounding tissue and analyze the cellular changes that occurred within lymph nodes [23].…”

Section: Introductionmentioning

confidence: 99%

Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps

et al. 2020

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Vascularized lymph node transfer (VLNT) is a promising treatment modality for lymphedema; however, how lymphatic tissue responds to ischemia has not been well defined. This study investigates the cellular changes that occur in lymph nodes in response to ischemia and reperfusion. Lymph node containing superficial epigastric artery-based groin flaps were isolated in Prox-1 EGFP rats which permits real time identification of lymphatic tissue by green fluorescence during flap dissection. Flaps were subjected to ischemia for either 1, 2, 4, or 8 hours, by temporarily occluding the vascular pedicle. Flaps were harvested after 0 hours, 24 hours, or 5 days of reperfusion. Using EGFP signal guidance, lymph nodes were isolated from the flaps and tissue morphology, cell apoptosis, and inflammatory cytokines were quantified and analyzed via histology, immunostaining, and rtPCR. There was a significant increase in collagen deposition and tissue fibrosis in lymph nodes after 4 and 8 hours of ischemia compared to 1 and 2 hours, as assessed by picrosirius red staining. Cell apoptosis significantly increased after 4 hours of ischemia in all harvest times. In tissue subject to 4 hours of ischemia, longer reperfusion periods were associated with increased rates of CD3 + and CD45 + cell apoptosis. rtPCR analysis demonstrated significantly increased expression of CXCL1/GRO-α with 2 hours of ischemia and increased PECAM-1 and TNF-α expression with 1 hour of ischemia. Significant cell death and changes in tissue morphology do not occur until after 4 hours of ischemia; however, analysis of inflammatory biomarkers suggests that ischemia reperfusion injury can occur with as little as 2 hours of ischemia.

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Impacts of arterial ischemia or venous occlusion on vascularized groin lymph nodes in a rat model

Cited by 14 publications

References 32 publications

Short-term molecular and cellular effects of ischemia/reperfusion on vascularized lymph node flaps in rats

Short-term molecular and cellular effects of ischemia/reperfusion on vascularized lymph node flaps in rats

Lower Limb Lymphedema Patients Can Still Benefit from Supermicrosurgical Lymphaticovenous Anastomosis (LVA) after Vascularized Lymph Node Flap Transfer (VLNT) as Delayed Lymphatic Reconstruction—A Retrospective Cohort Study

Ischemia and reperfusion injury in superficial inferior epigastric artery-based vascularized lymph node flaps

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