Diminished lung injury with vascular adhesion molecule-1 blockade in choline-deficient ethionine diet-induced pancreatitis.
BACKGROUND
Lung injury in severe acute pancreatitis is mediated by infiltrating leukocytes. Our laboratory has previously demonstrated that acute lung injury in acute pancreatitis results in an up-regulation of vascular adhesion molecule-1 (VCAM-1) cell surface receptor expression on pulmonary vascular endothelium and neutrophil sequestration. The objective of this study was to determine whether blocking expression of VCAM-1 in acute pancreatitis would modify acute pulmonary injury.


METHODS
Young female mice were fed a choline-deficient ethionine (CDE) supplemented diet to induce acute pancreatitis. After initiation of the diet, one group (acute pancreatitis treated [n = 18]) was treated with blocking doses (2.35 mg/kg) of monoclonal anti-VCAM-1 receptor antibody (Ab) at 48, 96, and 120 hours. A second group (acute pancreatitis treated control [n = 5]) was treated with a similar dose of an isotypic control for VCAM-1 (nonbinding Ab) at the same time points. A third group (acute pancreatitis untreated [n = 12]) received a CDE diet, and a fourth group (control [n = 11]) received standard food with no Ab treatment. All animals were killed at 144 hours. The dual radiolabeled monoclonal Ab method was used to quantitate VCAM-1 cell surface expression in lung tissue. Lung injury was assessed histologically, and apoptosis was detected by transferase-mediated deoxyuridine triphosphate nick end labeling assay. Pulmonary leukocyte sequestration was determined by myeloperoxidase (MPO) assay and CD18 staining.


RESULTS
Pulmonary VCAM-1 cell surface expression was significantly increased in animals with acute pancreatitis when compared to controls (P <.001) and was reduced to near control levels in acute pancreatitis treated animals. On histologic examination, treated animals with acute pancreatitis exhibited significantly less lung injury and apoptosis than did untreated animals with acute pancreatitis. Leukocyte sequestration and MPO activity were significantly reduced in the treated animals with pancreatitis compared to untreated animals with pancreatitis (P <.0001) or acute pancreatitis treated controls (P <.03).


CONCLUSIONS
Blocking VCAM-1 on pulmonary vascular endothelium decreases leukocyte adherence and recruitment into the lung, hence reducing lung injury in severe acute pancreatitis. Clinically, VCAM-1 antagonism may be an important adjunct to evolving therapy for distant organ injury in severe acute pancreatitis.
Callicutt
Christopher S
CS
Department of Surgery, University of Tennessee Health Science Center, 956 Court Avenue, Suite A202, Memphis, TN 38163, USA.
Sabek
Omaima
O
Fukatsu
Kazuhiko
K
Lundberg
Andrew H
AH
Gaber
Lillian
L
Wilcox
Henry
H
Kotb
Malak
M
Gaber
A Osama
AO
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D017209:Apoptosis; D002794:Choline / Q000494:pharmacology; D004032:Diet; D005001:Ethionine / Q000494:pharmacology; D007150:Immunohistochemistry; D008168:Lung / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D051379:Mice; D010179:Pancreas / Q000473:pathology; D010195:Pancreatitis / Q000150:complications* / Q000276:immunology / Q000473:pathology; D009195:Peroxidase / Q000378:metabolism; D011014:Pneumonia / Q000209:etiology* / Q000276:immunology / Q000473:pathology; D015854:Up-Regulation; D019010:Vascular Cell Adhesion Molecule-1 / Q000276:immunology* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D019010:Vascular Cell Adhesion Molecule-1; D009195:Peroxidase; D000681:Amylases; D002794:Choline; D005001:Ethionine