Pentoxifylline attenuates pulmonary inflammation and neutrophil activation in experimental acute pancreatitis.
OBJECTIVE
Acute pancreatitis (AP) is associated with a systemic inflammatory response. Pentoxifylline (PTX) has been shown to attenuate neutrophil activation and end-organ injury in shock states such as hemorrhage and sepsis. We hypothesized that PTX would down-regulate AP-induced lung injury.


METHODS
Sprague-Dawley rats underwent catheterization of the pancreatic duct. Acute pancreatitis (n = 7) and AP/PTX animals (n = 7) received a retrograde infusion of 3.5% sodium taurocholate and intravenous treatment with normal saline or normal saline and PTX (25 mg/kg), respectively. Pulmonary neutrophil degranulation and sequestration were determined by zymography and detection of myeloperoxidase. Nuclear factor kappa B and mitogen-activated protein kinase phosphorylation was determined by Western blot. Cytokine-induced neutrophil chemoattractant was quantified by enzyme linked immunosorbent assay.


RESULTS
Pulmonary histologic injury scores were attenuated in the AP/PTX group (P < 0.05). Plasma amylase levels remained unchanged. Pentoxifylline produced a significant decline in myeloperoxidase content and matrix metalloproteinase activity (P < 0.05). The increase in the phosphorylation of pulmonary nuclear factor kappa B, p38 mitogen-activated protein kinase, and extracellular-related signal kinase 1/2 observed after AP was not demonstrated with PTX (P < 0.05). Pentoxifylline supplementation reduced pulmonary cytokine-induced neutrophil chemoattractant levels by 50% (P < 0.05).


CONCLUSIONS
Pentoxifylline significantly attenuated histologic lung injury, pulmonary neutrophil activity, and proinflammatory signaling in a severe model of AP. Therefore, PTX may serve as an adjunct for the treatment of the inflammatory complications of severe AP.
de Campos
Tercio
T
Division of Trauma and Surgical Critical Care, Department of Surgery, University of California School of Medicine, San Diego, CA, USA.
Deree
Jessica
J
Martins
Joilson O
JO
Loomis
William H
WH
Shenvi
Edna
E
Putnam
James G
JG
Coimbra
Raul
R
D000208:Acute Disease; D000681:Amylases / Q000097:blood; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D054360:Chemokine CXCL1 / Q000378:metabolism; D004195:Disease Models, Animal; D008168:Lung / Q000187:drug effects* / Q000201:enzymology / Q000276:immunology / Q000473:pathology; D008297:Male; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D018375:Neutrophil Activation / Q000187:drug effects*; D010195:Pancreatitis / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy* / Q000201:enzymology / Q000276:immunology; D010431:Pentoxifylline / Q000494:pharmacology*; D009195:Peroxidase / Q000378:metabolism; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010766:Phosphorylation; D011014:Pneumonia / Q000201:enzymology / Q000209:etiology / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013656:Taurocholic Acid; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000893:Anti-Inflammatory Agents; D054360:Chemokine CXCL1; C513297:Cxcl1 protein, rat; D016328:NF-kappa B; D010726:Phosphodiesterase Inhibitors; D013656:Taurocholic Acid; D009195:Peroxidase; D048051:p38 Mitogen-Activated Protein Kinases; D000681:Amylases; D020778:Matrix Metalloproteinase 2; C522363:Mmp2 protein, rat; D020780:Matrix Metalloproteinase 9; D010431:Pentoxifylline