Perioperative fluid therapy impairs lymphatic pump function in male rats

Physiological Reports · 2025-06-01 · 1 citations

Because of its life-saving benefits, perioperative IV fluid therapy remains a cornerstone of medical treatment. However, it also induces sustained edemagenic stress. The resulting persistent interstitial edema-excessive fluid accumulation in the interstitium-significantly delays recovery and worsens patient outcomes. Therefore, to gain a detailed understanding of the lymphatic functional consequences of perioperative fluid therapy, this study aimed to test the hypothesis that perioperative IV fluid therapy compromises lymphatic pump function within 3 days after major surgery. Following a midline laparotomy, animals received IV fluid therapy over 48 h during recovery (FLTP). Three days post-surgery, mesenteric lymphatic vessels from FLTP and sham surgery (CTRL) animals were isolated, and lymphatic pump function was assessed in vitro. The transmural pressure-pump flow and circumferential length-wall tension relationships of FLTP vessels were altered-contraction frequency and normalized pump flow and active and passive wall tensions were significantly lower than CTRL. In vessels from another group of animals with surgically produced mesenteric venous hypertension to induce sustained edemagenic stress, only the pressure-pump flow relationship was altered similarly to FLTP. These results demonstrate the detrimental effects of perioperative fluid therapy on lymphatic pumping, which is essential for restoring interstitial fluid pressure and resolving edema and inflammation.

Short-chain fatty acids of the intestinal microbiota reduce mesenteric lymphatic pumping

Physiology · 2023-05-01

Short-chain fatty acids (SCFAs; acetate (AC), propionate (PP), and butyrate (BT)) are the primary metabolites of the intestinal microbiota. In addition to being an epithelial energy source, SCFAs exert numerous local effects, including maintenance of the epithelial barrier integrity and protection against inflammation, and are commonly assumed beneficial. It is also well understood that mesenteric lymphatic function is vital for normal gut health; impaired pumping leads to interstitial accumulation of fluid and immune cells, inducing intestinal edema and inflammation. Mesenteric lymphatic vessels are exposed to significantly high concentrations of SCFAs, yet the acute effects of SCFAs on lymphatic function have remained unexplored. Following earlier reports of SCFAs-induced relaxation of vascular smooth and cardiac muscle, in the present study, we tested the hypothesis that AC, PP, and BT reduce lymphatic pumping.Following our recently reported methods, pumping was characterized in vitro using rat mesenteric lymphatic vessels. Briefly, isolated vessels were cannulated, perfused, and bathed with warmed APSS. Following 60-min initial equilibration, in spontaneously contracting vessels, the effects of acute treatment with AC (10 mM), PP (10 mM), BT (10 mM), or AC+PP+BT were determined. In an additional set of vessels, the effects of short-chain fatty acid receptor antagonists (GLPG0974, FFAR2 antagonist, 1 μM and ((R)-3-Hydroxybutyric acid, FFAR3 antagonist, 1 μM) on lymphatic acute responses to AC+PP+BT were determined. Lymphatic responses were characterized using contraction frequency (CF), normalized stroke volume (difference in diastolic and systolic volume normalized to passive volume, NSV), normalized pump flow (CF*NSV, NPF), and diastolic tone (difference in passive and diastolic diameters normalized to passive diameter, DT).Treatment with AC, PP, or BT alone decreased CF and NPF significantly. Accordingly, CF and NPF were also lowered significantly after the combined treatment with the three SCFAs. Nevertheless, both indices were completely restored after FFAR2 and FFAR3 inhibition. Changes in NSV and DT after treatment with AC, PP, or BT, however, were not significant.To our knowledge, the present study is the first to demonstrate adverse chronotropic effects of the three primary SCFAs produced by intestinal microbiota on lymphatic pumping. The lymphatic responses are consistent with reports of reduced heart rate and cardiac contractile indices more than the dilation of blood vessels induced by SCFAs. Further studies are needed to reconcile the apparent conflict between the beneficial effects of SCFAs and the damaging effects of impaired lymphatic pumping. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The DeBakey Executive Research Leadership Program Bridges the Depth of Experienced Leaders with the Breadth of Emerging Leaders

The FASEB Journal · 2022-05-01

Although new investigators leading research operations may be well trained to conduct research, they often have limited practical experience leading research teams. To address this unmet need, the Aggie Research Program (ARP) was developed in 2016 to advance the research careers of graduate students and postdoctoral scholars by connecting them with teams of undergraduates seeking research experiences. The requirements for graduate students and postdoctoral scholars to become “Team Leaders” are simple: they must get permission from their faculty mentors to participate, have an active research project, select and train a team of 3‐8 undergraduates, meet with their team once a week, and submit short weekly progress reports. To earn certification of completion, they must also attend monthly Team Leader meetings where they discuss best practices in leadership and complete a “Best Practices Report” to document their innovations to address challenges. This scalable structure allowed the ARP program to grow exponentially until a critical mass was achieved for Team Leaders to congregate in different affinity groups, which could then be formalized in distinct research leadership programs with different disciplinary or vocational focuses. In 2020, the ARP partnered with the Michael E. DeBakey Institute at Texas A&M University to create the DeBakey Executive Research Leadership program for graduate students, postdoctoral scholars, and junior faculty. This program leverages the combined 50 years of leadership experience of the Director and the Executive Director of the DeBakey Institute to distill a set of “research leadership principles” consistent with successful leadership careers at Texas A&M. These principles are introduced at the beginning of each Team Leader meeting to stimulate discussion of current challenges faced by Team Leaders. By bridging the deep experience of established leaders with the broad experience of a diverse cohort of emerging leaders, the DeBakey Executive Research Leadership Program structures a resilient, mutually supportive community that has grown during a pandemic. In the fall of 2021, it not only provided research leadership training for 47 Team Leaders, but also created research opportunities for 229 undergraduates. This multilevel, experience‐based training program provides a strategy to fill a critical gap in research training that cannot be filled by standard leadership or mentoring workshops which are typically too general, too short in duration, and too removed from the context in which they were originally developed.

Dichotomous effects of in vivo and in vitro ionizing radiation exposure on lymphatic function

AJP Heart and Circulatory Physiology · 2022 · 8 citations

• Biology
• Chemistry
• Cell biology

Earlier studies leading to the common belief that lymphatic vessels are radioresistant either did not characterize lymphatic pumping, deemed necessary for the resolution of edema and inflammation, or did it in vivo. By characterizing pumping in vitro, the present study, for the first time, demonstrated that lymphatic pumping was impaired in vessels irradiated in vivo and enhanced in vessels irradiated in vitro. Furthermore, the pathways implicated in ionizing radiation-induced blood vessel damage did not mediate lymphatic responses.

Effects of Acetate on Mesenteric Lymphatic Pump Function

The FASEB Journal · 2022-05-01

Pump function of mesenteric lymphatic vessels (MLVs) is essential for active transport of intestinal lymph and lipids from the gut to the venous circulation. MLV pump function is also critical for transport of immune cells in the GI tract, which account for almost 70% of the body’s immune cells. Short‐chain fatty acids (SCFAs)—the metabolites of the intestinal microbiota—are absorbed rapidly across the intestinal epithelial barrier and their concentration reaches 1‐100 mM in the intestinal tissues. There is a growing interest in the effects SCFAs on blood vessels. Blood vessel studies using acetate, the most abundant SCFA in peripheral circulation, reported that vasodilation induced by acetate mediates the blood pressure lowering effects of acetate. Furthermore, nitric oxide (NO) pathway was identified to mediate the acetate‐induced vasodilation. MLVs are exposed to significantly higher SCFA concentrations (as high as those in the intestinal tissues) in the undiluted lymph compared to the blood vessels. However, the effects of SCFAs on lymphatic vessel function have yet to be investigated thoroughly. Therefore, the purpose of the present study was to evaluate our hypothesis that acetate induces lymphatic dilation and decreases lymphatic pump function. MLVs were isolated from male Sprague Dawley rats and cannulated and perfused with warm APSS. Transmural pressure was set to 3 cmH 2 O and MLVs were allowed to equilibrate. In spontaneously contracting vessels, changes in pump function in response to cumulative concentrations of acetate (10 ‐8 to 10 ‐2 M) were determined. In separate MLVs, pump function at three transmural pressures (3, 5 and 7 cmH 2 O; selected randomly) was evaluated before and after incubating the MLVs with acetate (10 mM). Additionally, in another set of MLVs, lymphatic pump function at three transmural pressures (3, 5 and 7 cmH 2 O; selected randomly) was evaluated before and after incubating the MLVs with N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME; 100 µM) and again after incubating the MLVs with L‐NAME (100 µM) + acetate (10 mM). The dose‐response study revealed that acetate led to decrease in lymphatic contraction frequency and calculated active lymph flow in a dose‐dependent manner. IC50 of the dose‐response curve was 1mM and lymphatic pumping was completely abolished at 50 mM concentration. Lymphatic contraction frequency and calculated active lymph flow were significantly decreased at all transmural pressures. Lymphatic stroke volume normalized to passive volume and diastolic tone were not significantly altered by acetate. Blockade of the NO pathway with L‐NAME did not restore the acetate‐induced decrease in lymphatic contraction frequency at all transmural pressures. Consistent with the effects of acetate on the blood vessels, acetate decreased lymphatic pump function in a dose‐dependent manner. However, the findings suggest that the NO pathway, reported to mediate blood vessel responses to acetate, does not mediate lymphatic responses to acetate. Two different pathways mediating acetate‐induced vasodilation in blood and lymphatic vessels may enable regulation of blood or lymphatic vessel function independently.

In Vitro Irradiation of Lymphatic Vessels Enhances Lymphatic Pump Function

The FASEB Journal · 2022-05-01

Active lymphatic pumping is critical for propulsion of lymph against a pressure gradient as well as transport of lipids and immune cells to the central venous circulation. When lymphatic pumping is impaired, diminished lymph flow leads to interstitial edema, immune cell accumulation and sustained inflammation. However, a majority of radiation biology research has primarily focused on the effects of ionizing radiation (IR) on blood vessels. These studies reported that IR induces imbalance between vaso‐dilatory and ‐constrictive pathways and impairs vascular tone. Only a handful of the studies have investigated the acute effects of IR on lymphatic vessels. Furthermore, the studies evaluating IR‐induced changes in lymphatic tone and pumping in vivo are limited because, in addition to the intrinsic contractility of the lymphatic muscle, lymphatic tone and pumping in vivo is modulated by a variety of substances present in the luminal lymph and the surrounding interstitial fluid. Therefore, the goal of the present study was to characterize the effects of IR on lymphatic tone and pumping independent of the confounding effects of IR on the other tissues. Mesenteric lymphatic vessels (MLVs), isolated from male Sprague Dawley rats, were randomly divided into SHAM and IR groups and were placed in chilled APSS. MLVs from the IR group were then irradiated with X‐rays at 10 Gray Dose. Immediately after irradiation, MLVs from both groups were placed in chilled APSS until further use. MLVs were then cannulated and perfused with warm APSS. Lymphatic pumping was assessed in spontaneously contracting vessels. Role of nitric oxide (NO) and cyclooxygenase (COX) pathways was evaluated by assessing pump function in separate MLVs before and after incubation in N(ω)‐nitro‐L‐arginine methyl ester (L‐NAME; 100 µM) and Indomethacin (INDO; 10 µM). Evaluation of the lymphatic pumping in response to changes in transmural pressure revealed significantly increased contraction frequency and calculated active lymph flow in IR MLVs compared to those in SHAM MLVs. However, stroke volume normalized to passive volume and diastolic tone were not significantly different between the IR and SHAM MLVs. The increase in contraction frequency in IR MLVs was partially restored by the blockade of COX pathways with INDO. Blockade of NOS with L‐NAME, however, led to further increase in contraction frequency of IR MLVs, which was significantly higher than that in SHAM MLVs. Early studies investigating the IR effects on lymphatic endothelial cells reported that lymphatic endothelium is resistant to IR. Conflicting findings of the in vivo lymphatic studies have further confounded the insights into the lymphatic responses to IR. It has been widely believed that lymphatic vessels are unaffected by IR, and therefore, the role of the lymphatic system‐ the other half of the circulatory system, in radiation injury has been mostly ignored. However, it is evident from the findings of the present study that lymphatic vessels are indeed affected by IR. Furthermore, IR‐induced increase in contraction frequency observed in the present study suggests that lymphatic acute responses to IR differ from the blood vessel responses.

Adaptation of the hepatic transudation barrier to sinusoidal hypertension

AJP Regulatory Integrative and Comparative Physiology · 2020 · 3 citations

• Medicine
• Pathology
• Internal medicine

The role of the hepatic transudation barrier in determining ascites volume and protein content in chronic liver disease is poorly understood. Therefore, the purpose of the present study was to characterize how chronic sinusoidal hypertension impacts hepatic transudation barrier properties and the transudation rate. The suprahepatic inferior vena cava was surgically constricted, and animals were exposed to either short-term (SVH; 2-3 wk) or long-term venous hypertension (LVH; 5-6 wk). Compared with SVH, LVH resulted in lower peritoneal fluid pressure, ascites volume, and ascites protein concentration. The transudation barrier protein reflection coefficient was significantly higher, and the transudation barrier hydraulic conductivity, transudation rate, and transudate-to-lymph protein concentration ratio were significantly lower in LVH animals compared with SVH animals. The sensitivity of transudation rates to acute changes in interstitial fluid pressures was also significantly lower in LVH animals compared with SVH animals. In contrast, there was no detectable difference in hepatic lymph flow rate or sensitivity of lymph flow to acute changes in interstitial fluid pressures between SVH and LVH animals. Taken together, these data suggest that decreased hepatic transudation barrier permeability to fluid and protein and increased reflection coefficient led to a decrease in the hepatic contribution to ascites volume. The present work, to the best of our knowledge, is the first to quantify an anti-ascites adaptation of the hepatic transudation barrier in response to chronic hepatic sinusoidal hypertension.

Pandemic Preparedness and Response in the Age of Technology

OakTrust (Texas A&M University Libraries) · 2020-07-06

The Fourth Annual White Paper from the Scowcroft Institute of International Affairs at The Bush School of Government & Public Service at Texas A&M University

Global leadership at the crossroads: Are we prepared for the next pandemic?

OakTrust (Texas A&M University Libraries) · 2018-05-01

"In this report, the Scowcroft Institute of International Affairs at The Bush School of Government & Public Service at Texas A&M University outlines eight priority areas and their accompanying recommended action items to address vulnerabilities in the current pandemic preparedness and response system. Collectively, they represent issues the international community should address in order to establish pandemic preparedness and response capabilities." -- p. 5.

Anti‐Ascites Adaptation of Liver to Sinusoidal Hypertension

The FASEB Journal · 2017-04-01

The hepatic capsule is highly permeable to water and proteins. Increases in sinusoidal pressure as low as 1 mmHg have been reported to significantly elevate transudation across the capsule into the peritoneal cavity under normal conditions. However, despite the fact that hepatic sinusoidal and interstitial fluid pressures are significantly elevated with cirrhosis, transudation across the capsule is minimal and there is a lack of ascites. Because hepatic lymphatic vessels and thoracic ducts are enlarged and lymph flows are several times higher than normal levels, lack of ascites in compensated cirrhosis has been commonly ascribed to enhanced hepatic lymph flow. However, changes in capsular properties have yet to be investigated thoroughly. Therefore, the purpose of this study was to evaluate our hypothesis that sustained sinusoidal hypertension leads to decrease in capsular permeability and transudation rate. Capsular hydraulic conductance, reflection coefficient, transudation rate and hepatic lymph flow rate were evaluated following short‐term (2–3 weeks; StSH) and long term (5–6 weeks; LtSH) exposure to sinusoidal hypertension. Although hepatic capsular transudation and lymph flow rates were elevated in both groups, capsular hydraulic conductance and the transudation rate were lower and the reflection coefficient was higher in LtSH. Furthermore, comparison of hepatic interstitial fluid pressure‐lymph flow and hepatic interstitial fluid pressure‐transudation relationships revealed decreased sensitivity of capsular transudation to changes in hepatic interstitial fluid pressure in LtSH. Taken together, these findings suggest that adaptation of hepatic capsule precedes the enlargement of the hepatic lymphatic vessels and may primarily be responsible for the lack of ascites in compensated cirrhosis.