| 61. |
- Hwaiz, Rundk, et al.
(författare)
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Rac1 signaling regulates sepsis-induced pathologic inflammation in the lung via attenuation of Mac-1 expression and CXC chemokine formation.
- 2013
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Ingår i: Journal of Surgical Research. - : Elsevier BV. - 1095-8673 .- 0022-4804. ; 183:2, s. 798-807
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Tidskriftsartikel (refereegranskat)abstract
- Excessive neutrophil recruitment is a major feature in septic lung damage although the signaling mechanisms behind pulmonary infiltration of neutrophils in sepsis remain elusive. In the present study, we hypothesized that Rac1 might play an important role in pulmonary neutrophil accumulation and tissue injury in abdominal sepsis. Male C57BL/6 mice were treated with Rac1 inhibitor NSC23766 (5 mg/kg) before cecal ligation and puncture (CLP). Bronchoalveolar lavage fluid and lung tissue were collected for the quantification of neutrophil recruitment and edema and CXC chemokine formation. Blood was collected for the determination of Mac-1 on neutrophils and proinflammatory compounds in plasma. Gene expression of CXC chemokines and tumor necrosis factor alpha was determined by quantitative reverse transcription-polymerase chain reaction in alveolar macrophages. Rac1 activity was increased in lungs from septic animals, and NSC23766 significantly decreased pulmonary activity of Rac1 induced by CLP. Administration of NSC23766 markedly reduced CLP-triggered neutrophil infiltration, edema formation, and tissue damage in the lung. Inhibition of Rac1 decreased CLP-induced neutrophil expression of Mac-1 and pulmonary formation of CXC chemokines. Moreover, NSC23766 abolished the sepsis-evoked elevation of messenger RNA levels of CXC chemokines and tumor necrosis factor alpha in alveolar macrophages. Rac1 inhibition decreased the CLP-induced increase in plasma levels of high mobility group protein B1 and interleukin 6, indicating a role of Rac1 in systemic inflammation. In conclusion, our results demonstrate that Rac1 signaling plays a key role in regulating pulmonary infiltration of neutrophils and tissue injury via regulation of chemokine production in the lung and Mac-1 expression on neutrophils in abdominal sepsis. Thus, targeting Rac1 activity might be a useful strategy to protect the lung in abdominal sepsis.
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| 62. |
- Jeppsson, Bengt, et al.
(författare)
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Evidence-based medicine in HBP surgery: Is there any?
- 2005
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Ingår i: HPB. - : Elsevier BV. - 1477-2574 .- 1365-182X. ; 7:3, s. 197-200
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Tidskriftsartikel (refereegranskat)abstract
- Background. Evidence-based medicine (EBM) has become widely accepted as a basis for clinical decision in many fields of medicine. This review examines the specific role of EBM in hepato-biliary and pancreatic (HBP) surgery. EBM relies on four main sources, including clinical guidelines, meta-analyses, primary information and clinical experience. Randomized controlled trials (RCTs) constitute the cornerstone of EBM and a recent study reported that there are relatively few RCTs evaluating the effectiveness of surgical therapies and procedures (1,530 out of 45,342 or 3.4% in five leading surgical journals) and only a few in HBP surgery. Although the effort must be to implement EBM as far as possible in HBP surgery, there are several obstacles to conducting RCTs in HBP surgery, including problems associated with standardization of surgical skills, sham-operations often impossible to perform, and the general applicability of specific findings may be uncertain.Discussion. This paper will provide two relevant examples of EBM in HBP surgery in patients with hepatic metastases and pancreatic adenocarcinoma, illustrating some problems but also the potential of introducing EBM in HBP surgery. In the future, our effort must be devoted to implementing EBM in applicable areas of HBP surgery but also remembering that in certain areas accumulated knowledge from observational studies, including drainage of abscesses and surgical treatment of intestinal obstruction, may have similar or even higher clinical value than RCTs.
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| 63. |
- Jeppsson, Bengt, et al.
(författare)
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Use of Probiotics as Prophylaxis for Postoperative Infections
- 2011
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Ingår i: Nutrients. - : MDPI AG. - 2072-6643. ; 3:5, s. 604-612
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Forskningsöversikt (refereegranskat)abstract
- Postoperative bacterial infections are common despite prophylactic administration of antibiotics. The wide-spread use of antibiotics in patients has contributed to the emergence of multiresistant bacteria. A restricted use of antibiotics must be followed in most clinical situations. In surgical patients there are several reasons for an altered microbial flora in the gut in combination with an altered barrier function leading to an enhanced inflammatory response to surgery. Several experimental and clinical studies have shown that probiotics (mainly lactobacilli) may reduce the number of potentially pathogenia bacteria (PPM) and restore a deranged barrier function. It is therefore of interest to test if these abilities of probiotics can be utilized in preoperative prophylaxis. These factors may be corrected by perioperative administration of probiotics in addition to antibiotics. Fourteen randomized clinical trials have been presented in which the effect of such regimens has been tested. It seems that in patients undergoing liver transplantation or elective surgery in the upper gastrointestinal tract prophylactic administration of different probiotic strains in combination with different fibers results in a three-fold reduction in postoperative infections. In parallel there seems to be a reduction in postoperative inflammation, although that has not been studied in a systematic way. The use of similar concepts in colorectal surgery has not been successful in reducing postoperative infections. Reasons for this difference are not obvious. It may be that higher doses of probiotics with longer duration are needed to influence microbiota in the lower gastrointestinal tract or that immune function in colorectal patients may not be as important as in transplantation or surgery in the upper gastrointestinal tract. The favorable results for the use of prophylactic probiotics in some settings warrant further controlled studies to elucidate potential mechanisms, impact on gut microbiota and influence on clinical management. The use of probiotics must be better delineated in relation to type of bacteria, dose and length of administration.
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| 64. |
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| 65. |
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| 66. |
- Johnson, Louis Banka, et al.
(författare)
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Radiation enteropathy and leucocyte-endothelial cell reactions in a refined small bowel model
- 2004
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Ingår i: BMC Surgery. - : Springer Science and Business Media LLC. - 1471-2482. ; 4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Leucocyte recruitment and inflammation are key features of high dose radiation-induced tissue injury. The inflammatory response in the gut may be more pronounced following radiotherapy due to its high bacterial load in comparison to the response in other organs. We designed a model to enable us to study the effects of radiation on leucocyte-endothelium interactions and on intestinal microflora in the murine ileum. This model enables us to study specifically the local effects of radiation therapy. METHOD: A midline laparotomy was performed in male C57/Bl6 mice and a five-centimetre segment of ileum is irradiated using the chamber. Leucocyte responses (rolling and adhesion) were then analysed in ileal venules 2 - 48 hours after high dose irradiation, made possible by an inverted approach using intravital fluorescence microscopy. Furthermore, intestinal microflora, myeloperoxidase (MPO) and cell histology were analysed. RESULTS: The highest and most reproducible increase in leucocyte rolling was exhibited 2 hours after high dose irradiation whereas leucocyte adhesion was greatest after 16 hours. Radiation reduced the intestinal microflora count compared to sham animals with a significant decrease in the aerobic count after 2 hours of radiation. Further, the total aerobic counts, Enterobacteriaceae and Lactobacillus decreased significantly after 16 hours. In the radiation groups, the bacterial count showed a progressive increase from 2 to 24 hours after radiation. CONCLUSION: This study presents a refinement of a previous method of examining mechanisms of radiation enteropathy, and a new approach at investigating radiation induced leucocyte responses in the ileal microcirculation. Radiation induced maximum leucocyte rolling at 2 hours and adhesion peaked at 16 hours. It also reduces the microflora count, which then starts to increase steadily afterwards. This model may be instrumental in developing strategies against pathological recruitment of leucocytes and changes in intestinal microflora in the small bowel after radiotherapy.
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| 67. |
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| 68. |
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| 69. |
- Khan, Umama, et al.
(författare)
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Neutrophil extracellular traps in colorectal cancer progression and metastasis
- 2021
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Ingår i: International Journal of Molecular Sciences. - : MDPI AG. - 1661-6596 .- 1422-0067. ; 22:14
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Forskningsöversikt (refereegranskat)abstract
- Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.
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| 70. |
- Klintman, Daniel, et al.
(författare)
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Important role of p-selectin for leukocyte recruitment, hepatocellular injury, and apoptosis in endotoxemic mice.
- 2004
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Ingår i: Clinical and Diagnostic Laboratory Immunology. - 1071-412X. ; 11:1, s. 56-62
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Tidskriftsartikel (refereegranskat)abstract
- Leukocyte recruitment in the liver includes a two-step procedure in which selectin-dependent leukocyte rolling is a prerequisite for subsequent CD18-dependent leukocyte firm adhesion in postsinusoidal venules. However, the roles of the individual selectins in leukocyte rolling and adhesion, hepatocellular injury, and apoptosis remain elusive. Therefore, we examined the pathophysiological role of P-, E-, and L-selectin in male C57BL/6 mice challenged with lipopolysaccharide (LPS) and D-galactosamine (Gal) by use of intravital microscopy of the liver microcirculation. In control animals, administration of LPS-Gal provoked reproducible hepatic damage, including marked increases of leukocyte recruitment, liver enzymes, and hepatocyte apoptosis and reduced sinusoidal perfusion. Interestingly, pretreatment with an anti-P-selectin antibody (RB40.34) markedly reduced leukocyte rolling and firm adhesion by 65 and 71%, respectively. Moreover, interference with P-selectin function significantly improved sinusoidal perfusion and reduced the increase in liver enzymes by 49 to 84% in endotoxemic mice. Moreover, the activity of caspase-3 and the number of apoptotic hepatocytes were significantly reduced by 55 and 54%, respectively, in RB40.34-treated animals. In contrast, administration of an anti-E-selectin antibody (10E9.6) and an anti-L-selectin antibody (Mel-14) did not protect against endotoxin-induced leukocyte responses or hepatic injury. In conclusion, our novel findings document a principal role of P-selectin in mediating leukocyte rolling, a precondition to the subsequent firm adhesion of leukocytes in liver injury. Furthermore, our novel data demonstrate that inhibition of P-selectin function reduces hepatocellular injury and apoptosis, suggesting a causal relationship between leukocyte recruitment on one hand and hepatocellular injury and apoptosis on the other hand. Based on these findings, it is suggested that P-selectin may be an important therapeutic target in endotoxin-induced liver injury.
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