Involvement of exosomes in lung inflammation associated with experimental acute pancreatitis

Abstract

A frequent complication of acute pancreatitis is the lung damage associated with the systemic inflammatory response. Although various pro‐inflammatory mediators generated at both local and systemic levels have been identified, the pathogenic mechanisms of the disease are still poorly understood. In recent years, exosomes have emerged as a new intercellular communication system able to transfer encapsulated proteins and small RNAs and protect them from degradation. Using an experimental model of taurocholate‐induced acute pancreatitis in rats, we aimed to evaluate the role of exosomes in the extent of the systemic inflammatory response. Induction of pancreatitis increased the concentration of circulating exosomes, which showed a different proteomic profile to those obtained from control animals. A series of tracking experiments using PKH26‐stained exosomes revealed that circulating exosomes effectively reached the alveolar compartment and were internalized by macrophages. In vitro experiments revealed that exosomes obtained under inflammatory conditions activate and polarize these alveolar macrophages towards a pro‐inflammatory phenotype. Interestingly, the proteomic analysis of circulating exosomes during acute pancreatitis suggested a multi‐organ origin with a relevant role for the liver as a source of these vesicles. Tracking experiments also revealed that the liver retains the majority of exosomes from the peritoneal cavity. We conclude that exosomes are involved in the lung damage associated with experimental acute pancreatitis and could be relevant mediators in the systemic effects of pancreatitis. Copyright © 2016 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via Toll‐like receptor 4

“…recipient animals. A similar finding was reported in blood exosomes from a rat acute pancreatitis model, such as increased proinflammatory cytokines production in AMs (17). Collectively, our findings show that the inflammatory stress of host cells induces generation of hyperinflammatory exosomes that signal danger to the recipient cells in the distant organs.…”

“…As we expected, ML exosomes released after T/HS, but not preshock exosomes or supernatant of ML, induced ALI in vivo. Several studies support the theory that the biologic activity of exosomes is likely altered by the pathophysiological conditions of the host (17,(41)(42)(43). Particularly, exosomes have been defined as a novel inflammatory factor in sepsis.…”

“…We have recently identified the presence of exosomes in rat ML and demonstrated that exosomes in postshock ML have the ability to trigger NF-kB activation and proinflammatory cytokine production in monocytes and macrophages in vitro (14). Interestingly, recent studies have demonstrated that exosomes isolated from tumor cell lines as well as several body fluids (i.e., serum, amniotic fluid, liver cirrhosis ascites, and malignant ascites) induce proinflammatory cytokine production in monocytes and macrophages via TLR-dependent signaling pathways (15)(16)(17).…”

REG3β modifies cell tumor function by impairing extracellular vesicle uptake

“…The same experiment was performed with MIA PaCa-2 cells, which were incubated with labeled THP1-EVs for 2 h. REG3β concentrations used in this experiment were within the range of plasma REG3β levels reported in pancreatic cancer patients 32 . The concentration of EVs was selected according to previous in vitro studies 33, 34 .…”

Inhibition of the CD40/CD40L complex protects mice against ALI‐induced pancreas degradation

“…Therefore, pancreatitis appears to share certain pathophysiological features similar to that of ALI/TRALI. Some findings, indeed, evoke a narrow frontier between pancreatitis and ALI …”