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Title: Modulation of lymphatic function during sepsis
Author: Reem, Uzma
ISNI:       0000 0004 5366 4652
Awarding Body: University of Sheffield
Current Institution: University of Sheffield
Date of Award: 2015
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Rationale & Hypothesis: Lymphatic vessel function becomes impaired during sepsis; with stagnation of lymphatic flow and dysfunction of the mechanisms regulating contractility, which contribute to tissue oedema. Angiopoietin-1 (Ang-1) is a growth hormone that regulates vascular permeability via Tie-2 and is known to have anti-inflammatory effects on the blood vasculature, however, any effects on lymphatics have not yet been characterised. We hypothesised that inflammatory mediators released during sepsis compromise lymphatic function which is improved by Ang-1. Methodology: Mesenteric collecting lymphatics (80-200 µm) were dissected from male Sprague Dawley rats (150-200g) and mounted on a pressurised myograph system at 3cm H2O. Responses to inflammatory stimuli were measured up to 2.5h following exposure to LPS (50 µg/ml), TNF-α (10-500ng/ml) and IL-1β (10-100ng/ml). Role of NO in mediating effects of TNF-α was assessed by measuring contractility of TNF-α treated vessels in the presence of L-NAME (1mM). To determine the effects of Ang-1 on vessel function, changes in spontaneous contractions were measured for 2.5h in response to 250 ng/ml recombinant human Ang-1 in the absence and presence of 10ng/ml TNF-α. Findings & Conclusions: There was minimal change in frequency of contractions from baseline at the end of 2.5h with Ang-1 alone (1.33±0.66) and in combination with TNF-α (0.66±1.76) compared to the reduced contractions induced by TNF-α alone (-9±1.87), suggesting a protective effect of Ang-1. Ang-1 alone slightly decreased amplitude (10±16%) with minimal change in combination with TNF-α (2±5%) compared to increased amplitude induced by TNF-α alone (15±23%). TNF-α did not alter frequency in presence of L-NAME, suggesting that effects may be NO mediated. Ang-1 does not alter spontaneous contractions but improves contraction frequency and amplitude in inflamed lymphatic vessels. Our study elucidates the effects of potent inflammatory mediators on lymphatic vessel function and demonstrates a protective role of Ang-1 in vessel function during sepsis.
Supervisor: Hellewell, Paul G. ; Brown, Nicola J. Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID:  DOI: Not available