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The transient activation of inflammatory networks is required for adipose tissue remodeling including the "browning" of white fat in response to stimuli such as β3-adrenergic receptor activation. In this process, white adipose tissue acquires thermogenic characteristics through the recruitment of so-called beige adipocytes. We investigated the downstream signaling pathways impinging on adipocyte progenitors that promote de novo formation of adipocytes. We showed that the Jak family of kinases controlled TGFβ signaling in the adipose tissue microenvironment through Stat3 and thereby adipogenic commitment, a function that was required for beige adipocyte differentiation of murine and human progenitors. Jak/Stat3 inhibited TGFβ signaling to the transcription factors Srf and Smad3 by repressing local Tgfb3 and Tgfb1 expression before the core transcriptional adipogenic cascade was activated. This pathway cross-talk was triggered in stromal cells by ATGL-dependent adipocyte lipolysis and a transient wave of IL-6 family cytokines at the onset of adipose tissue remodeling induced by β3-adrenergic receptor stimulation. Our results provide insight into the activation of adipocyte progenitors and are relevant for the therapeutic targeting of adipose tissue inflammatory pathways., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background: Transrectal natural orifice specimen extraction (NOSE) avoids abdominal organ retrieval during laparoscopic procedures and may reduce surgical trauma. However, this has not been proven clinically and transrectal peritoneal contamination is feared to cause infectious complications. This experimental study was designed to evaluate inflammatory response and peritoneal contamination after transrectal NOSE versus mini-laparotomy., Methods: 24 German Landrace pigs underwent transrectal NOSE (N = 12) or mini-laparotomy (N = 12) for standardized extraction of water-instilled balloon. Blood samples were taken for analysis of leucocytes, CRP, IL-6, IL-10, and TNFα at 6, 12, 24, 48, 72 h as well as 7 and 14 days postoperatively. After 14 days laparoscopy was performed to inspect the abdomen and for microbiological swab sampling., Results: Leucocytes were higher in the NOSE group at 72 h (19.3 ± 3.9/nl vs. 15.8 ± 4.2/nl, p = 0.046). IL-6 was lower in the NOSE group at day 7 (165 ± 100/nl vs. 306 ± 70/nl, p = 0.030). No difference was found comparing inflammatory parameters at all other time points. No difference was found regarding peritoneal contamination, which was 58.3% (7/12) in the NOSE group and 41.7% (5/12) in the MiniLap group (p = 0.414)., Conclusions: The results suggest a pronounced acute inflammatory response after transrectal NOSE compared to mini-laparotomy, while late cytokine response seems to be less after transrectal NOSE, which may reflect less intense wound healing process. Using standardized rectal decontamination and endolumenal colon occlusion transrectal NOSE seems to be safe and comparable to mini-laparotomy with regard to peritoneal contamination. Clinical evidence is needed now to weight transrectal NOSE against mini-laparotomy during laparoscopic surgery.

Therapeutic hypothermia is commonly used to improve neurological outcomes in patients after cardiac arrest. However, therapeutic hypothermia increases sepsis risk and unintentional hypothermia in surgical patients increases infectious complications. Nonetheless, the molecular mechanisms by which hypothermia dysregulates innate immunity are incompletely understood. We found that exposure of human monocytes to cold (32°C) potentiated LPS-induced production of TNF and IL-6, while blunting IL-10 production. This dysregulation was associated with increased expression of microRNA-155 (miR-155), which potentiates Toll-like receptor (TLR) signaling by negatively regulating Ship1 and Socs1. Indeed, Ship1 and Socs1 were suppressed at 32°C and miR-155 antagomirs increased Ship1 and Socs1 and reversed the alterations in cytokine production in cold-exposed monocytes. In contrast, miR-155 mimics phenocopied the effects of cold exposure, reducing Ship1 and Socs1 and altering TNF and IL-10 production. In a murine model of LPS-induced peritonitis, cold exposure potentiated hypothermia and decreased survival (10 vs. 50%; P < 0.05), effects that were associated with increased miR-155, suppression of Ship1 and Socs1, and alterations in TNF and IL-10. Importantly, miR-155-deficiency reduced hypothermia and improved survival (78 vs. 32%, P < 0.05), which was associated with increased Ship1, Socs1, and IL-10. These results establish a causal role of miR-155 in the dysregulation of the inflammatory response to hypothermia., (© FASEB.)

Objective: This article reviews the current understanding of transient receptor potential ion channels (TRP channels) in health and disease., Background: Transient receptor potential ion channels are a group of 27 channels that are expressed in all tissues. These channels play important roles in surgically important problems, such as chronic pain, susceptibility to infection, hypothermia, and some cancers., Methods: A literature search was performed. This review focuses on the role of TRP channels in a few surgically important disease processes, such as pain, inflammation, airway diseases, and malignant melanomas. In addition, we discuss some of the structural properties that are important for the activation of TRP channels., Results: TRPA1 and TRPV1 are expressed on pain fibers and play an important role in the development of chronic pain, such as chemotherapy-related neuropathic pain. Deletion of TRPA1 and TRPV1 suppresses the development of chronic pain, and blockers of TRPA1 and TRPV1 show promise as a new class of painkillers. Furthermore, several TRP channels are expressed on immune cells. Macrophages express at least 3 different TRP channels, and the properly balanced activation of all these channels together allows normal macrophage function. Deletion of any of these channels results in impaired macrophage function and increased susceptibility to infection. Because several of these TRP channels on macrophages are temperature sensitive, they may comprise the link for hypothermia-related infectious complications in trauma, and to a lesser degree, in elective surgical patients., Conclusions: Transient receptor potential ion channels are involved in several surgically important disease processes. Activation or blockade of these channels offers new therapeutic opportunities. Pharmacologic activation or blockade of TRP channels may offer new treatment options in surgical patients for the management of pain and infections.

Background: Peritonitis is a common cause of surgical sepsis. The failure of the host to mount an appropriate immune response contributes to persistence of the infection. We investigated the role microRNAs may play in this failed immune response., Methods: Klebsiella pneumoniae was injected intraperitoneally in mice. Weight loss was used to predict clinical outcome. Peritoneal exudate cells (PECs) and supernatant were collected. RNA from PECs was run on screening microRNA array cards to determine gene expression, and validated by single assay analysis. Cytokine levels in supernatant were assayed by enzyme-linked immunosorbent assay., Results: Despite similar bacterial levels, PEC counts were higher in the predicted death group. The predicted deaths had higher levels of proinflammatory tumor necrosis factor-α/IL-6 and significantly lower levels of interleukin-10. MiR-221 was up-regulated in both the predicted death and predicted survivor groups. Five miRNAs were up-regulated in the predicted survivor group compared with normal controls., Conclusion: Higher PEC counts and proinflammatory cytokines in the predicted death group indicates an exaggerated inflammatory response, with lower IL-10 levels despite similar bacterial counts. There were two dysregulated miRNAs with transcriptional targets that may explain our results. A more balanced immune response with an appropriate counter inflammatory response may be important for improving survival., (Copyright © 2013 Mosby, Inc. All rights reserved.)

Background and Study Aims: The risk of infectious complications due to peritoneal contamination is a major concern and inhibits the widespread use of transrectal NOTES. A standardized rectal washout with a reversible colon occlusion device in situ has previously shown potential in reducing peritoneal contamination. The aim of this study was to compare the peritoneal contamination rate and inflammatory reaction for transrectal cholecystectomy after ideal rectal preparation (trCCE) and standard laparoscopic cholecystectomy (lapCCE) in a porcine survival experiment.Methods: Twenty pigs were randomized to trCCE (n = 10) or lapCCE (n = 10). Before trCCE, rectal washout was performed with saline solution. A colon occlusion device was then inserted and a second washout with povidone-iodine was performed. The perioperative course and the inflammatory reaction (leukocytes, C-reactive protein) were compared. At necropsy, 14 days after surgery the abdominal cavity was screened for infectious complications and peritoneal swabs were obtained for comparison of peritoneal contamination.Results: Peritoneal contamination was lower after trCCE than after lapCCE (0/10 vs. 6/10; p = 0.003). No infectious complications were found at necropsy in either group and postoperative complications did not differ (p = 1.0). Immediately after the procedure, leukocytes were higher after lapCCE (17.0 ± 2.7 vs. 14.6 ± 2.3; p = 0.047). Leukocytes and C-reactive protein showed no difference in the further postoperative course. Intraoperative complications and total operation time (trCCE 114 ± 32 vs. 111 ± 27 min; p = 0.921) did not differ, but wound closure took longer for trCCE (31.5 ± 19 vs. 13 ± 5 min; p = 0.002).Conclusions: After standardized rectal washout with a colon occlusion device in situ, trCCE was associated without peritoneal contamination and without access-related infectious complications. Based on the findings of this study, a randomized controlled clinical study comparing clinical outcomes of trCCE with lapCCE should be conducted. [ABSTRACT FROM AUTHOR]

Objective: To investigate whether warming to normal body temperature or to febrile range temperature (39°C) is able to reverse the detrimental effects of hypothermia. Background: Unintentional intraoperative hypothermia is a well-described risk factor for surgical site infections but also sepsis. We have previously shown that hypothermia prolongs the proinflammatory response whereas normothermia and especially febrile range temperature enhance the antiinflammatory response. Methods: Primary human monocytes were isolated from healthy volunteers. After stimulation with LPS (Lipopolysaccharide), the monocytes were exposed to 32°C for 3 hours or 6 hours and then warmed at either 37°C or 39°C for the remaining 33 hours or 36 hours, respectively. Tumor necrosis factor α, interleukin 10, and the expression of miR-155 and miR-101 were assessed at 24 hours and 36 hours. Results: Warming to 37°C does not normalize monocyte cytokine secretion within 36 hours, whereas warming to 39°C partially reverses the effects of hypothermia on monocyte function. Both miR-155 and miR-101 were suppressed after the warming episode. However, 39°C had a stronger suppressive effect than 37°C. The duration of hypothermia and the warming temperature seem to be critical for a full reversibility of the effects of hypothermia. Conclusion: Warming to normal body temperature (37°C) does not restore normal monocyte function in vitro. These data suggest that hypothermic patients should be warmed to febrile range temperatures. Furthermore, febrile range temperatures should be investigated as a means to modulate the inflammatory response in patients with systemic infections. [ABSTRACT FROM AUTHOR]