Therapeutic Methylprednisolone and Infimab Decrease the Severity of Organ Dysfunction in Pancreatic Duct Ligation Model of Severe Acute Pancreatitis in Wistar Rats

Abstract

Introduction: There is no standardized, widely used model of severe acute pancreatitis (SAP) with organ failure. This may limit drug development in SAP. Dysregulated and hyperimmune responses are the root cause for organ failure in SAP. We established a rat model of SAP with organ failure and evaluated directly translatable, clinically relevant parameters of organ dysfunction. We also evaluated the effects of therapeutic administration of methylprednisolone (MP) and TNF-α antibody infimab (Infliximab biosimilar) on the severity of experimental SAP induced by the ligation of the main pancreatic duct in rats. Methods: SAP was induced in adult male Wistar rats (250-350 g) by ligating the main pancreatic duct proximal to the biliopancreatic junction. One-hour after the procedure, therapeutic medication was administered intraperitoneally. Experiments were done in duplicate(batches of 3 rats/group) in sham surgery, SAP, SAP+MP, and SAP+infimab groups. At 0 (pre-intervention) and 48 hours (post-intervention), invasive BP, heart rate, serum amylase, lactate, paO2, SpO2, pH, renal and liver function were measured. Rats were sacrificed at 48 hours and the harvested pancreas, kidney and lung tissues were assessed histopathologically. Results: There was a significant increase in serum amylase level (p=0.019) and histopathological scores (p=0.003) in the SAP group as compared to sham surgery with no significant effect of either MP or Infimab (amylase:p = 0.211, histopathological score:p = 0.103). Both MP and Infimab significantly prevented a fall in BP and decrease in SpO2 following induction of SAP compared to the vehicle control (Table1). Conclusions: Therapeutic administration of MP or Infimab ameliorates the systemic inflammation and organ dysfunction associated with SAP in rats.Tabled 1EP02A-024SAP (Vehicle control)SAP + IP MethylprednisoloneSAP + IP Infimabp value for between group comparison of change following intervention (vehicle control vs MP vs Infimab )Change* following Interventionp value of change*Change following Interventionp value of change*Change* following Interventionp value of change*Amylase (IU/L)2681 (1072 to 3753)0.0043260 (1490 to 9960)0.0621457.5 (370 to 2350)0.0310.211Mean BP (mmHg)-15.4 (-17 to -13.4)0.004-3.6 (-6 to 6)0.688-19.3 (-28.6 to -3.9)0.0940.023Heart Rate (beats/min)-47 (-57.1 to -36.5)0.004-6.4 (-31.3 to -2.3)0.313-15.1 (-37.3 to 1.8)0.4380.133Blood Lactate (mmol/L)2.3 (0.7 - 2.7)0.0091.8 (1.2 - 2.3)0.0312.05 (0.2 - 2.3)0.0630.845SpO2 (%)-3.5 (-9.5 to -1.9)0.008-0.5 (-5.9 to 2.9)0.688-0.4 (-0.2 to 0)0.5840.176pO2 (mmHg)-5 (-31.9 to -0.9)0.074-3.7 (-65.6 to 9.5)0.563-6.7 (-16.1 to 1.9)0.2190.786*change refers to difference between the pre - intervention and post - intervention values Open table in a new tab *change refers to difference between the pre - intervention and post - intervention values