Acute pancreatitis is an inflammatory disorder of the pancreas. Its presentation ranges from self-limiting disease to acute necrotizing pancreatitis (ANP) with multiorgan failure and a high mortality (1). Currently, the medical treatment for this disease still remains supportive and directed to prevent the systemic complications. Polyethylene glycols (PEGs) are non-immunogenic, non-toxic, and water-soluble chemicals composed of repeating units of ethylene glycol (2). They are widely accepted by the Food and Drug Administration for use in food, cosmetic, and pharmaceuticals. In clinical, they are currently used as additives to organ preservation solutions to attenuate the damage associated with cold ischemia-reperfusion (3). The present study explores the effect of 35-kDa PEG (PEG35) administration on reducing the severity of ANP and associated lung injury. Male Wistar rats were housed in a controlled environment following all European Union regulatory standards for animal experimentation (Directive 2010/63/EU on the protection of animals used for scientific purposes). The Ethical Committee for Animal Experimentation (CEEA, ethic approval number: 211/18, University of Barcelona, 11/04/2018) approved the animal experiments. Rats were anesthetized with an intraperitoneal injection of pentobarbital (50 mg/kg). Then, ANP was induced by injection of 5% sodium taurocholate into the biliopancreatic duct.  PEG35 was administered intravenously in a single dose (10 mg/kg) either prophylactically or therapeutically. Three hours after ANP induction, animals were euthanized, and samples were evaluated. Histopathological examination of pancreatic and lung tissue was accomplished choosing randomly microscopic fields. Secondarily, plasma lipase activity was measured to determine the severity of the pancreas damage. To evaluate the inflammatory response, gene expression of pro-inflammatory cytokines (IL-6, IL-1β, and TNF-α) and chemokine (CXCL-2) and the changes in the presence of myeloperoxidase and adhesion molecule levels (p-selectin and ICAM-1) were determined in both the pancreas and the lung. To study the cell death, lactate dehydrogenase (LDH) activity and apoptotic cleaved caspase-3 localization were determined in plasma and in both the pancreatic and lung tissue, respectively. Lipase activity was diminished with the PEG35 pre-treatment in both pancreas and lung, while the therapeutic administration was not able to reduce the pancreas injury. However, PEG35 reduced the histopathological injuries in lung tissue when it was administered therapeutically. We also showed the levels of proinflammatory cytokines and chemokine were significantly decreased when PEG35 had been administrated after ANP induction. In addition, therapeutic administration of PEG35 lessened neutrophil recruitment and extravasation in the lung, indicating a significant protection against the systemic complications. To further study, we observed that therapeutic treatment with PEG35 significantly reduced the expression of P- selectin and ICAM-1 in the lung. Finally, on inflammation induced cell-death, the therapeutic treatment with PEG35 significantly reduced LDH activity and the cleaved caspase-3 levels in the lung. Collectively, our data highlight the potential use of PEG35 as a treatment to ameliorate the severity of the inflammatory damage in acute pancreatitis and to modulate its progression to a lethal condition (4).