Further reports indicate administration of anti-neutrophil serum significantly reduces microvascular permeability and myeloperoxidase increase in the lungs of both experimental diet-induced as well as cerulein-induced pancreatitis model [18,19]. A very recent report indicates that during AP, neutrophils that are recruited to the pancreas may reverse migrate back into the circulation and further contribute to ALI. Another interesting report examined the process that neutrophils use to eliminate invading microorganisms by expelling nuclear DNA and histones to form extracellular web-like structures called neutrophil extracellular traps NETs.
These NETs were depleted by administration of DNase I enzyme to mice and revealed decreased neutrophil infiltration, reduced tissue damage and inflammation in the pancreas and lung, and decreased levels of blood amylase, macrophage inflammatory protein-2, interleukin 6, and high-mobility groups protein-1 [21]. Migration of neutrophils into the lungs is a characteristic feature of ALI; however, native macrophages that reside in the pulmonary alveoli and interstitium are also thought to play a crucial role in the pathogenesis of ALI during severe acute pancreatitis [].
The cross talk of neutrophils and macrophages results in the release of a number of cytokines and chemokines that further progress to ALI. In general, there are two known types of macrophages, M1 and M2. M1 macrophages, also known as classically activated macrophages, are crucial effector cells and eliminate micro-organisms [26].
M2 macrophages, also known as alternatively activated macrophages, are mainly involved in regulating the resolution of inflammatory responses [27]. In the lung, these macrophages are further sub-grouped into alveolar, pleural, interstitial and intravascular macrophages [].
Krausgruber et al. However, the molecular mechanisms of IRF5 in macrophage polarization should be further studied [29]. Down-regulation of TNF-associated factor 6 TRAF-6 is associated with progression of acute pancreatitis complicating lung injury in mice [13]. IL-6 is a very important pro-inflammatory cytokine involved in inflammation and immune responses [45] and is known to be elevated in the serum during acute pancreatitis as compared to normal individuals [46,47].
The use of neutralizing anti-CINC antibody in a cerulein-induced experimental model of acute pancreatitis revealed protective effects in the lungs [48]. Macrophage migration inhibitory factor MIF is released by T lymphocytes, monocytes, macrophages and epithelial cells and is a pro-inflammatory cytokine and an important regulator of innate immunity [49]. MIF is evolving as a critical key molecule in the pathogenesis of acute pancreatitis and pre-treatment with anti-MIF antibodies improved the survival of rats with AP [51].
IL, a member of the IL cytokine family, showed anti-inflammatory properties like IL and protects mice from acute pancreatitis induced by cerulein and by a choline-deficient diet supplemented with DL-ethionine CDE [53]. A similar protection by IL is also observed in severe acute pancreatitis SAP -associated lung injury induced by L-arginine in an experimental model.
IL mediates its protective effect by increasing the expression level of anti-apoptosis genes, such as Bcl-2 and Bcl-xL, through the STAT3 signaling pathway [54]. Acute lung injury and acute respiratory distress syndrome in acute pancreatitis remains an unsolved issue and needs more research and resources to develop effective treatment therapy. However, recent efforts have tested several molecules in experimental models and showed promising results as treatment options. The significance of some of these molecules we present in this review.
Kynurenine 3-monooxygenase KMO is an enzyme of tryptophan metabolism and catalyzes the conversion of L-Kynurenine to 3-hydroxy-L-Kynurenine which causes oxidative stress [55] and induces apoptosis [56]. KMO is an important branch point in the kynurenine pathway and an attractive drug target for immunological, neurodegenerative, and neuro-inflammatory diseases [57].
Kynurenine is reported to contribute to acute lung injury in an acute pancreatitis model of rats and increased levels of Kynurenine have been reported in the blood of severe acute pancreatitis patients [58]. Interestingly, a very recent study by Mole and coworkers has generated global KMO knockout mice which are protected against extra pancreatic tissue injury to lung, kidney, and liver in experimental acute pancreatitis-multiple organ dysfunction syndrome AP-MODS.
These findings indicate KMO inhibition may serve as a novel therapeutic strategy in the treatment of AP-MODS including lung injury and provide a new avenue for drug discovery to cure the pathogenesis of AP-induced multiple organ failure.
Pulmonary apoptosis is an important pathogenic mechanism of acute lung injury during acute pancreatitis. Lung protective ventilatory strategies are of paramount importance to improve outcome of patients of AP with ARDS and therefore effective coordination between gastroenterologists and intensivists is needed for effective management of these patients.
Keywords: Acute lung injury; Acute pancreatitis; Fluid collection; Mechanical ventilation; Pancreatic necrosis. Abstract Development of organ failure is one of the major determinants of mortality in patients with acute pancreatitis AP. Publication types Review. We offer online appointment scheduling for video and in-person appointments for adult and pediatric primary care and many specialties. Skip to content Appointments Close Appointments Schedule your appointment online for primary care and many specialties.
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