Blocking Pulmonary ICAM-1 Expression Ameliorates Lung Injury in Established Diet-Induced Pancreatitis
| Autor: | A. Osama Gaber, Malak Kotb, Lillian W. Gaber, Andrew H. Lundberg, Scott Callicutt, Kazuhiko Fukatsu, Kenneth A. Kudsk, Henry G. Wilcox |
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| Rok vydání: | 2001 |
| Předmět: |
Mice
Inbred Strains Lung injury Proinflammatory cytokine Sepsis Mice Animals Medicine Lung Pancreas business.industry Cell adhesion molecule Respiratory disease Antibodies Monoclonal Original Articles Intercellular Adhesion Molecule-1 medicine.disease Up-Regulation Neutrophil Infiltration Pancreatitis Acute Disease Immunology Acute pancreatitis Female Surgery business Selectin |
| Zdroj: | Annals of Surgery. 233:213-220 |
| ISSN: | 0003-4932 |
| DOI: | 10.1097/00000658-200102000-00010 |
| Popis: | The high rates of death and complications associated with severe acute pancreatitis (AP) stem from an overwhelming inflammatory response that can cause injury to distant organs such as lung tissue. 1,2 Patients with severe AP develop pulmonary dysfunction, which clinically resembles the acute respiratory distress syndrome of sepsis. 3 Despite advances in the diagnosis and treatment of inflammatory pancreatic disease, supportive care remains the only treatment for patients with pulmonary complications. 4,5 The role of adhesion molecules in the development of AP-associated organ injury has been verified in several experimental models using mice that are genetically deficient of selectin or intracellular adhesion molecules (ICAM-1), as well as in models where these molecules are blocked with specific monoclonal antibodies (mAbs). For example, Werner et al 6 highlighted the potential for adhesion molecule inhibitors in pancreatitis-associated lung injury. Frossard et al 7 showed that inhibiting neutrophil action reduces the severity of the lung injury that occurs in mice with AP. They also showed that AP is less severe when induced in mice deficient in ICAM-1 compared with their normal counterparts. Together, these results implicate both the neutrophil and the ICAM-1 receptor as significant mediators of local and distant injury in AP. 7–9 Starting with the discovery of an overproduction of inflammatory cytokines in AP, our laboratory has demonstrated that systemic manifestations of AP can be ameliorated by cytokine blockade given before 10,11 or immediately after the onset of experimental AP. However, because of our interest in devising clinically relevant therapies, our focus has shifted to more downstream events in AP. Despite their utility in experimental models, therapies such as antiproteases, somatostatin, and antiplatelet activating factor administered late in the disease course have little effect on clinical outcome. 12 Similarly, anticytokine treatment given later in the disease course appears to be of little benefit. 13 One of the major effects by which cytokine upregulation mediates distant injury is by the adhesion molecule overexpression on endothelial cells. Specifically, adhesion molecules mediate leukocyte activation and can instigate lung injury. 7,14 We reasoned that intervening in the events downstream to cytokine activation might afford effective tools for clinical disease management. In the current study, we used a novel approach to demonstrate the significance of adhesion molecule blockade in ameliorating the lung manifestations associated with AP. Specifically, we evaluated lung injury in mice treated with anti-ICAM-1 mAb several days after the onset of AP. So far, other investigators have reported that blocking ICAM-1 expression before the onset of AP diminishes the severity of the disease, 6 thus confirming the role of ICAM-1-mediated organ injury. However, the clinical relevance of anti-ICAM-1 treatment after the onset of pancreatitis remained questionable until now. This work is the first demonstration of a delayed treatment during AP that ameliorates pancreatitis-associated pulmonary injury without affecting the inflammatory process seen in the pancreas. |
| Databáze: | OpenAIRE |
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