Abstract
Intestinal ischemia and reperfusion (I/R) is a potentially life-threatening condition, sometimes leading to a systemic inflammatory response and the potential development of the multiple organ dysfunction syndrome. The overall aim of the thesis was to study the effects of intestinal I/R on pulmonary function with special emphasis on removal of excess alveolar fluid, pulmonary endothelial barrier permeability, leukocyte accumulation and function, and possible therapeutic strategies to prevent the development of pulmonary injury following intestinal I/R. Intestinal I/R was induced by clamping of the superior mesenteric artery for 40-45 min in male Sprague-Dawley rats, after which reperfusion was allowed for up to 12 hours.
Results show that intestinal I/R leads to an inflammatory response locally as well as in the lungs, with increased tissue and plasma levels of TNF-alpha and MCP-1, neutrophil accumulation in intestinal and pulmonary tissue, and an increase in pulmonary phagocytic capacity. The results also demonstrate increased intestinal and pulmonary endothelial permeabilities, a decrease in pulmonary tissue blood content, disruption of normal alveolar type II epithelial cell morphology, and stimulation of alveolar fluid clearance (AFC) through a non-catecholamine dependent mechanism. Protective effects of NAC, a broad-acting antioxidant, administration before the onset of reperfusion indicates involvement of oxygen free radicals in intestinal I/R-induced macrophage activation and decreased blood content. TNF-alpha monoclonal antibodies administered before the onset of intestinal I/R decreased AFC stimulation, indicating the involvement of TNF-alpha in the AFC stimulation.
Inhibition of the tissue factor (TF) VIIa complex formation by FVIIa-inhibition can attenuate the inflammatory response that occurs in assocation with intestinal I/R. The selective Factor Xa-inhibitor fondaparinux did, however, not demonstrate a convincing anti-inflammatory effect. Such properties are though not to be excluded since very limited dose response data exists with regard to potential anti-inflammatory properties also for FXa-inhibition.
Results show that intestinal I/R leads to an inflammatory response locally as well as in the lungs, with increased tissue and plasma levels of TNF-alpha and MCP-1, neutrophil accumulation in intestinal and pulmonary tissue, and an increase in pulmonary phagocytic capacity. The results also demonstrate increased intestinal and pulmonary endothelial permeabilities, a decrease in pulmonary tissue blood content, disruption of normal alveolar type II epithelial cell morphology, and stimulation of alveolar fluid clearance (AFC) through a non-catecholamine dependent mechanism. Protective effects of NAC, a broad-acting antioxidant, administration before the onset of reperfusion indicates involvement of oxygen free radicals in intestinal I/R-induced macrophage activation and decreased blood content. TNF-alpha monoclonal antibodies administered before the onset of intestinal I/R decreased AFC stimulation, indicating the involvement of TNF-alpha in the AFC stimulation.
Inhibition of the tissue factor (TF) VIIa complex formation by FVIIa-inhibition can attenuate the inflammatory response that occurs in assocation with intestinal I/R. The selective Factor Xa-inhibitor fondaparinux did, however, not demonstrate a convincing anti-inflammatory effect. Such properties are though not to be excluded since very limited dose response data exists with regard to potential anti-inflammatory properties also for FXa-inhibition.
| Original language | English |
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| Qualification | Doctor |
| Awarding Institution |
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| Supervisors/Advisors |
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| Award date | 2005 Mar 17 |
| Publisher | |
| ISBN (Print) | 91-85439-08-8 |
| Publication status | Published - 2005 |
Bibliographical note
Defence detailsDate: 2005-03-17
Time: 13:00
Place: Lecture room 3, Central building, Lund University Hospital, Lund
External reviewer(s)
Name: Revhaug, Arthur
Title: Professor
Affiliation: University Hospital Northern Norway, Tromso, Norway
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<div class="article_info">A Börjeson, XD Wang, Z Sun, R Wallén, X Deng, E Johansson and R Andersson. <span class="article_issue_date">2000</span>. <span class="article_title">Effects of N-acetylcysteine on pulmonary macrophage activity after intestinal ischemia and reperfusion in rats.</span> <span class="journal_series_title">Dig Surg</span>, <span class="journal_volume">vol 17</span> <span class="journal_pages">pp 379-389</span>.</div>
<div class="article_info">A Börjesson, A Norlin, XD Wang, R Andersson and HG Folkesson. <span class="article_issue_date">2000</span>. <span class="article_title">TNFalpha stimulates alveolar liquid clearance during intestinal ischemia-reperfusion in rats.</span> <span class="journal_series_title">Am J Physiol Lung Cell Mol Physiol</span>, <span class="journal_pages">pp L3-L12</span>.</div>
<div class="article_info">A Börjesson, K Olanders, X Zhao, R Wallén, X Wang and R Andersson. <span class="article_issue_date"></span>. <span class="article_title">Pulmonary inflammatory response and morphological changes following intestinal ischemia and reperfusion injury in rats.</span> <span class="journal_series_title">Scand J Gastroenterol.</span>, (submitted)</div>
<div class="article_info">K Olanders, A Börjesson, X Zhao and R Andersson. <span class="article_issue_date"></span>. <span class="article_title">Effects of anticoagulant treatment on intestinal ischemia and reperfusion injury in rats.</span> <span class="journal_series_title">Acta Anaesth Scand</span>, (accepted)</div>
Subject classification (UKÄ)
- Surgery
Free keywords
- reperfusion injury
- intestinal ischemia
- pulmonary injury
- endothelium
- cytokines
- alveolar fluid clearance
- leukocytes
- orthopaedics
- Surgery
- traumatology
- ortopedi
- Kirurgi
- traumatologi