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. 1998 Aug;43(2):232–239. doi: 10.1136/gut.43.2.232

A monoclonal anti-interleukin 8 antibody (WS-4) inhibits cytokine response and acute lung injury in experimental severe acute necrotising pancreatitis in rabbits

M Osman 1, J Kristensen 1, N Jacobsen 1, S Lausten 1, B Deleuran 1, M Deleuran 1, B Gesser 1, K Matsushima 1, C Larsen 1, S Jensen 1
PMCID: PMC1727205  PMID: 10189850

Abstract

Background—Interleukin 8 (IL-8) has recently been proposed to have an important role in mediating the development of the systemic sequelae associated with severe acute pancreatitis. 
Aims—To define the role of IL-8 in acute pancreatitis by neutralising its effects with a monoclonal anti-IL-8 antibody (WS-4), in a rabbit model of severe acute pancreatitis. 
Methods—Acute pancreatitis was induced by retrograde injection of 5% chenodeoxycholic acid into the pancreatic duct and duct ligation. Twenty rabbits were divided equally into two groups: acute pancreatitis controls received physiological saline and the treated group received WS-4, 30 minutes before induction of acute pancreatitis. 
Results—Pretreatment of animals with WS-4 resulted in significant down regulation of serum IL-8 and tumour necrosis factor α (TNF-α) from three to six hours after induction of acute pancreatitis (p=0.011 and 0.047 for IL-8 and 0.033 and 0.022 for TNF-α, respectively). In addition, a significant reduction in the CD11b and CD18 positive cells and the amount of interstitial neutrophil infiltration in the lungs from WS-4 treated animals was seen. In contrast, WS-4 did not alter the amount of pancreatic necrosis and the serum concentrations of amylase, lipase, calcium, and glucose. 
Conclusion—WS-4 cannot change the amount of pancreatic necrosis induced by injection of 5% bile acid, but does reduce the acute lung injury, presumably through inhibition of circulating IL-8 and TNF-α, and CD11b/CD18 in lung tissue. Therefore, a role of IL-8 in the progression of acute pancreatitis and the development of its systemic complications is suggested. 



Keywords: acute pancreatitis; rabbits; cytokines; anti-interleukin-8 antibody; acute lung injury

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Figure 1 .

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Survival curves for the 12 hour observation period. Fifty per cent of the untreated rabbits were alive at 9 h and only 40% at 12h, whereas 90% of WS-4 treated rabbits were alive at 12h (p<0.05). 


Figure 2 .

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(A) Serum TNF-α concentrations showing a biphasic curve in controls. with peaks at 3 and 9 h. Pretreatment with WS-4 resulted in a significant reduction in TNF-α concentrations from 3 to 9 h. (B) Serum concentratons of IL-8 increased steadily from 3 to 6 h in controls but a significant reduction was observed in the WS-4 treated group. 


Figure 3 .

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Output of ascitic fluid. 


Figure 4 .

Figure 4

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Semiquantitation of the granulocytic inflammatory response to necrosis in pancreatic tissue. 


Figure 5 .

Figure 5

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(A) Alveolar lung tissue from a control animal with grade 2 oedema and pronounced infiltration of the alveolar walls with inflammatory cells, which at high magnification are identified as mainly granulocytes. (B) Alveolar lung tissue from a WS-4 treated animal. There is grade 1 oedema and a less intense infiltration of the alveolar walls. Haematoxylin and eosin; original magnification ×190. 


Figure 6 .

Figure 6

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Number of granulocytes per high power field of lung sections (10 random fields), and semiquantitative evaluation of oedema and interstitial monocyte infiltration. 


Figure 7 .

Figure 7

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Distribution of CD18 expressing leucocytes in lungs of controls (A) and WS-4 treated animals (B). Streptavidin alkaline phosphatase technique, positive staining appears as red, counterstained with haematoxylin. Bar, 10 µm. 


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