The innate immune network is responsible for coordinating the initial defense against potentially noxious stimuli. This complex system includes anatomical, physical and chemical barriers, effector cells and circulating molecules that direct component and system interactions. Besides the direct effects of breaching pulmonary protective barriers, cyclic stretch generated during mechanical ventilation (MV) has been implicated in the modulation of the innate immunity. Evidence from recent human trials suggests that controlling MV-forces may significantly impact outcome in acute respiratory distress syndrome. In this paper, we explore the pertinent evidence implicating biotrauma caused by cyclic MV and its effect on innate immune responses. Introduction The natural or innate immune system is present in some form in most living organisms and consists of mechanisms for defending the host against foreign invaders and for healing injured tissues. We now know that many of the mechanisms of resistance to infection are also involved in the individual’s response to noninfectious foreign substances and environmental stresses, including mechanical stretch. Furthermore, mechanisms that normally protect individuals and eliminate foreign substances are themselves capable of causing tissue injury and disease. This inherent defense network includes anatomical, physical and chemical barriers, circulating molecules, cells with specific phagocytic or lytic abilities, and soluble mediators that orchestrate the activities of each component and their interactions with the acquired immune system. Normally, this is a well integrated system of host defense and preservation of self-integrity, in which numerous cells and molecules function cooperatively. However, dysregulation of the fine balance between proinflammatory and anti-inflammatory stimuli may explain the pathophysiologic processes that underlie syndromes such as sepsis and acute lung injury (ALI) [1]. Although patients undergoing positive pressure mechanical ventilation may have impaired lung function, and possibly impaired systemic immune defenses by virtue of their underlying lung pathology, further dysregulation of natural defenses occurs in these patients. The presence of an endotracheal tube bypassing natural upper airway defenses, decrease or loss of coughing, paralysis of bronchial ciliae, alterations in surfactant and phagocyte and epithelial defensins – a critical first line antibacterial defense mechanism – all contribute to impairment in host defense [2–4]. Apart from the direct effects of breaching pulmonary protective barriers, cyclic stretch generated during mechanical ventilation has been implicated in the modulation of the innate immune system. In this short review we revisit some of the pertinent evidence exploring the relationship between biotrauma caused by cyclic mechanical ventilation and its effect on innate immune responses. This is not intended to be a comprehensive and structured review of the Review Bench-to-bedside review: Biotrauma and modulation of the innate immune response Claudia C dos Santos1, Haibo Zhang2, Mingyao Liu3 and Arthur S Slutsky4 1Clinical Associate and Post Doctoral Fellow, Departments of Medicine and Critical Care Medicine, St. Michael’s Hospital, and Inter-Departmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada 2Assistant Professor, Departments of Medicine and Critical Care Medicine, St. Michael’s Hospital, and Inter-Departmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada 3Professor, Departments of Medicine and Critical Care Medicine, St. Michael’s Hospital, and Inter-Departmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada 4Vice President of Research, Departments of Medicine and Critical Care Medicine, St. Michael’s Hospital, and Inter-Departmental Division of Critical Care, University of Toronto, Toronto, Ontario, Canada Corresponding author: Arthur S Slutsky, arthur.slutsky@utoronto.ca Published online: 5 January 2005 Critical Care 2005, 9:280-286 (DOI 10.1186/cc3022) This article is online at http://ccforum.com/content/9/3/280 © 2005 BioMed Central Ltd

INTRODUCTION:Acute pancreatitis is a local inflammatory process that leads to a systemic inflammatory response in the majority of cases. Bacterial contamination has been estimated to occur in 30-40% of patients with necrotizing pancreatitis. Development of pancreatic necrosis depends mainly on the degree of inflammation and on the microvascular circulation of the pancreatic tissue. Activated protein C (APC) is known to inhibit coagulation and inflammation, and to promote fibrinolysis in patients with severe sepsis. We investigated the effects of APC on histopathology, bacterial translocation, and systemic inflammation in experimental acute necrotizing pancreatitis.MATERIALS AND METHOD:Forty-five male Sprague-Dawley rats were studied. Rats were randomly allocated to three groups. Acute pancreatitis was induced in group II (positive control; n = 15) and group III (treatment; n = 15) rats by retrograde injection of taurocholate into the common biliopancreatic duct. Group I rats (sham; n = 15) received an injection of normal saline into the common biliopancreatic duct to mimic a pressure effect. Group III rats were treated with intravenous APC 6 hours after induction of pancreatitis. Pancreatic tissue and blood samples were obtained from all animals for histopathological examination and assessment of amylase, tumor necrosis factor-alpha, and IL-6 levels in serum. Bacterial translocation to pancreas and mesenteric lymph nodes was measured.RESULTS:Acute pancreatitis developed in all groups apart from group I (sham), as indicated by microscopic parenchymal necrosis, fat necrosis and abundant turbid peritoneal fluid. Histopathological pancreatitis scores in the APC-treated group were lower than in positive controls (10.31 +/- 0.47 versus 14.00 +/- 0.52; P < 0.001). Bacterial translocation to mesenteric lymph nodes and to pancreas in the APC-treated group was significantly decreased compared with controls (P < 0.02 and P < 0.007, respectively). Serum amylase, tumor necrosis factor-alpha, and IL-6 levels were also significantly decreased in comparison with positive controls (P < 0.001, P < 0.04 and P < 0.001, respectively).CONCLUSION:APC improved the severity of pancreatic tissue histology, superinfection rates and serum markers of inflammation during the course of acute necrotizing pancreatitis.