title: Blocking pulmonary ICAM-1 expression ameliorates lung injury in established diet-induced pancreatitis.
abstract: OBJECTIVE
  To determine whether blocking the cell surface expression of intracellular adhesion molecules (ICAM-1) in established severe acute pancreatitis (AP) would ameliorate pulmonary injury.
  
  
  BACKGROUND
  Lung injury in AP is in part mediated by infiltrating leukocytes, which are directed to lung tissue by ICAM-l. The authors' laboratory has previously demonstrated that AP results in overproduction of inflammatory cytokines, upregulation of pulmonary ICAM-1 expression, and a concomitant infiltration of neutrophils, which results in lung injury.
  
  
  METHODS
  Young female mice were fed a choline-deficient/ethionine-supplemented diet to induce AP and were treated with a blocking dose of monoclonal antibody specific to the ICAM-1 receptor. Antibody treatment was administered at 72, 96, and 120 hours after beginning the diet, and all animals were killed at 144 hours. The degree of pancreatitis was evaluated by serum biochemical and tumor necrosis factor alpha levels as well as histology. The dual radiolabeled monoclonal antibody method was used to quantitate ICAM-1 cell surface expression in pulmonary tissue. Lung injury was assessed histologically and by determining lung microvascular permeability by measuring accumulated 125I-radiolabeled albumin. Pulmonary neutrophil sequestration was determined by the myeloperoxidase assay.
  
  
  RESULTS
  All mice developed severe AP, and pancreatic injury was equally severe in both treated and untreated groups. Pulmonary ICAM-1 expression was significantly upregulated in animals with AP compared with controls. Treatment with a blocking dose of anti-ICAM-1 antibody after the induction of AP resulted in inhibited ICAM-1 cell surface expression to near control levels. Compared to untreated animals with AP, mice treated with anti-ICAM-1 mice had significantly reduced histologic lung injury and neutrophil sequestration, and a decreased microvascular permeability by more than twofold.
  
  
  CONCLUSIONS
  These results demonstrate for the first time that treatment targeting the cell surface expression of ICAM-1 after the induction of AP ameliorates pulmonary injury, even in the face of severe pancreatic disease.
authors.affiliation: Department of Surgery, University of Tennessee, Memphis, USA.
authors.forename: A H
authors.initials: AH
authors.lastname: Lundberg
authors.forename: K
authors.initials: K
authors.lastname: Fukatsu
authors.forename: L
authors.initials: L
authors.lastname: Gaber
authors.forename: S
authors.initials: S
authors.lastname: Callicutt
authors.forename: M
authors.initials: M
authors.lastname: Kotb
authors.forename: H
authors.initials: H
authors.lastname: Wilcox
authors.forename: K
authors.initials: K
authors.lastname: Kudsk
authors.forename: A O
authors.initials: AO
authors.lastname: Gaber
mesh_terms: D000208:Acute Disease; D000818:Animals; D000911:Antibodies, Monoclonal; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000378:metabolism*; D008168:Lung / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D008815:Mice, Inbred Strains; D020556:Neutrophil Infiltration; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000473:pathology*; D015854:Up-Regulation
chemical_list: D000911:Antibodies, Monoclonal; D018799:Intercellular Adhesion Molecule-1