Modulating the Inflammatory Response to Wounds and Cancer Through Infection.
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ABSTRACT:
SUBMITTER: Lopez-Cuevas P
PROVIDER: S-EPMC8120001 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Sheikh Khalifa Medical City's (SKMC) Surgery Institute was identified as a high outlier in Surgical Site Infections (SSI) based on the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) - Semi-Annual Report (SAR) in January 2012. The aim of this project was to improve SSI rates through accurate wound classification. We identified SSI rate reduction as a performance improvement and safety priority at SKMC, a tertiary referral center. We used the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) best practice guidelines as a guide. ACS NSQIP is a clinical registry that provides risk-adjusted clinical outcome reports every six months. The rates of SSI are reported in an observed/expected ratio. The expected ratio is calculated based on the risk factors of the patients which include wound classification. We established a multidisciplinary SSI taskforce. The members of the SSI taskforce included the ACS NSQIP team members, quality, surgeons, nurses, infection control, IT, pharmacy, microbiology, and it was chaired by a colorectal surgeon. The taskforce focused on five areas: pre-op showering and hair removal, skin antisepsis, prophylactic antibiotics, peri-operative maintenance of glycaemia, and normothermia. We planned audits to evaluate our wound classification and our SSI rates based on the SAR. Our expected SSI rates in general surgery and the whole department were 2.52% and 1.70% respectively, while our observed SSI rates were 4.68% and 3.57% respectively, giving us a high outlier status with an odd's ratio of 1.72 and 2.03. Wound classifications were identified as an area of concern. For example, wound classifications were preoperatively selected based on the default wound classification of the booked procedure in the Electronic Medical Record (EMR) which led to under classifying wounds in many occasions. A total of 998 cases were reviewed, our rate of incorrect wound classification assignment was 36%, and the worst rates were in appendectomies (97%). Over time our incorrect wound classification decreased down to 22%, while at the same time our actual SSI wound occurrences per month and our odds ratio of SSI in the department have decreased an average of six to three per month. We followed the best practice guidelines of the ACS NSQIP. Accurate assessment of wound classification is necessary to make sure the expected SSI rates are not falsely high if wounds are under-classified. The present study shows that accurate wound classification in contaminated and dirty wounds can lead to lower odds ratio of SSI.
| S-EPMC4645904 | biostudies-other
Project description:Pseudomonas aeruginosa biofilm maintains and perturbs local host defense, hindering timely wound healing. Previously, we showed that P. aeruginosa suppressed S100A8/A9 of the murine innate host defense. We assessed the potential antimicrobial effect of S100A8/A9 on biofilm-infected wounds in a murine model and P. aeruginosa growth in vitro. Seventy-six mice, inflicted with a full-thickness burn wound were challenged subcutaneously (s.c.) by 10? colony-forming units (CFUs) of P. aeruginosa biofilm. Mice were subsequently randomized into two treatment groups, one group receiving recombinant murine S100A8/A9 and a group of vehicle controls (phosphate-buffered saline, PBS) all treated with s.c. injections daily for up to five days. Wounds were analyzed for quantitative bacteriology and contents of key inflammatory markers. Count of blood polymorphonuclear leukocytes was included. S100A8/A9-treatment ameliorated wound infection, as evaluated by quantitative bacteriology (p ? 0.05). In vitro, growth of P. aeruginosa was inhibited dose-dependently by S100A8/A9 in concentrations from 5 to 40 ?g/mL, as determined by optical density-measurement (OD-measurement) and quantitative bacteriology. Treatment slightly augmented key inflammatory cytokine Tumor Necrosis Factor-? (TNF-?), but dampened interferon-? (IFN-?) levels and blood polymorphonuclear count. In conclusion, topical S100A8/A9 displays remarkable novel immune stimulatory and anti-infective properties in vivo and in vitro. Importantly, treatment by S100A8/A9 provides local infection control. Implications for a role as adjunctive treatment in healing of chronic biofilm-infected wounds are discussed.
| S-EPMC5535852 | biostudies-other
Project description:To evaluate the role of TNIK in ECs and in regulation of disturbed flow and laminar flow, we established Human Aorta (HAECs) from two human donnors in which each target gene has been knocked down of TNIK by siRNA. We then performed gene expression profiling analysis using data obtained from RNA-seq of two different HAECs witt/without knocking down of TNIK under disturb flow and laminar flow for 24 hours
2024-02-09 | GSE236529 | GEO
Project description:BACKGROUND:AMP-activated Protein Kinase (AMPK) is a stress-activated kinase that protects against cardiomyocyte injury during ischemia and reperfusion. c-Jun N-terminal kinase (JNK), a mitogen activated protein kinase, is activated by ischemia and reperfusion. NF-?B is an important transcription factor involved in ischemia and reperfusion injury. METHODS AND RESULTS:The intrinsic activation of AMPK attenuates the inflammation which occurred during ischemia/reperfusion through the modulation of the JNK mediated NF-?B signaling pathway. Rat cardiac myoblast H9c2 cells were subjected to hypoxia and/or reoxygenation to investigate the signal transduction that occurred during myocardial ischemia/reperfusion. Mitochondrial function was measured by the Seahorse XF24 V7 PS system. Hypoxia treatment triggered AMPK activation in H9c2 cells in a time dependent manner. The inhibition of hypoxic AMPK activation through a pharmacological approach (Compound C) or siRNA knockdown of AMPK ? catalytic subunits caused dramatic augmentation in JNK activation, inflammatory NF-?B phosphorylation, and apoptosis during hypoxia and reoxygenation. Inhibition of AMPK activation significantly impaired mitochondrial function and increased the generation of reactive oxygen species (ROS) during hypoxia and reoxygenation. In contrast, pharmacological activation of AMPK by metformin significantly inhibited mitochondrial permeability transition pore (mPTP) opening and ROS generation. Moreover, AMPK activation significantly attenuated the JNK-NF-?B signaling cascade and inhibited mRNA and protein levels of pro-inflammatory cytokines, such as TNF-? and IL-6, during hyopoxia/reoxygenation in H9c2 cells. Intriguingly, both pharmacologic inhibition of JNK by JNK-IN-8 and siRNA knockdown of JNK signaling pathway attenuated NF-?B phosphorylation and apoptosis but did not affect AMPK activation in response to hypoxia and reoxygenation. CONCLUSIONS:AMPK activation modulates JNK-NF-?B signaling cascade during hypoxia and reoxygenation stress conditions. Cardiac AMPK activation plays a critical role in maintaining mitochondrial function and inhibiting the inflammatory response caused by ischemic insults.
| S-EPMC5960613 | biostudies-literature
Project description:BACKGROUND:Neuropathic pain (NeuP) is a chronic and challenging clinical problem, with little effective treatment. Resveratrol has shown neuroprotection by inhibiting inflammatory response in NeuP. Recently, the triggering receptor expressed on myeloid cells 2 (TREM2) expressed by microglia was identified as a critical factor of inflammation in nervous system diseases. In this study, we explored whether resveratrol could ameliorate neuroinflammation and produce anti-mechanical allodynia effects via regulating TREM2 in spared nerve injury rats, as well as investigated the underlying mechanisms. METHODS:A spared nerve injury (SNI) rat model was performed to investigate whether resveratrol could exert anti-mechanical allodynia effects via inhibiting neuroinflammation. To evaluate the role of TREM2 in anti-neuroinflammatory function of resveratrol, lentivirus coding TREM2 was intrathecally injected into SNI rats to activate TREM2, and the pain behavior was detected by the von Frey test. Furthermore, 3-methyladenine (3-MA, an autophagy inhibitor) was applied to study the molecular mechanisms of resveratrol-mediated anti-neuroinflammation using Western blot, qPCR, and immunofluorescence. RESULTS:The TREM2 expression and number of the microglial cells were significantly increased in the ipsilateral spinal dorsal horn after SNI. We found that intrathecal administration of resveratrol (300ug/day) alleviated mechanical allodynia; obviously enhanced autophagy; and markedly reduced the levels of interleukin-1?, interleukin-6, and tumor necrosis factor-? in the ipsilateral spinal dorsal horn after SNI. Moreover, the number of Iba-1+ microglial cells and TREM2 expression were downregulated after resveratrol treatment. Intrathecal administration of lentivirus coding TREM2 and/or 3-MA in those rats induced deficiencies in resveratrol-mediated anti-inflammation, leading to mechanical allodynia that could be rescued via administration of Res. Furthermore, 3-MA treatment contributed to TREM2-mediated mechanical allodynia. CONCLUSIONS:Taken together, these data reveal that resveratrol relieves neuropathic pain through suppressing microglia-mediated neuroinflammation via regulating the TREM2-autophagy axis in SNI rats.
| S-EPMC7576710 | biostudies-literature
Project description:The involvement of the enteric nervous system, which is a source of S100B, in Clostridioides difficile (C. difficile) infection (CDI) is poorly understood although intestinal motility dysfunctions are known to occur following infection. Here, we investigated the role of S100B in CDI and examined the S100B signaling pathways activated in C. difficile toxin A (TcdA)- and B (TcdB)-induced enteric glial cell (EGC) inflammatory response. The expression of S100B was measured in colon tissues and fecal samples of patients with and without CDI, as well as in colon tissues from C. difficile-infected mice. To investigate the role of S100B signaling in IL-6 expression induced by TcdA and TcdB, rat EGCs were used. Increased S100B was found in colonic biopsies from patients with CDI and colon tissues from C. difficile-infected mice. Patients with CDI-promoted diarrhea exhibited higher levels of fecal S100B compared to non-CDI cases. Inhibition of S100B by pentamidine reduced the synthesis of IL-1β, IL-18, IL-6, GMCSF, TNF-α, IL-17, IL-23, and IL-2 and downregulated a variety of NFκB-related genes, increased the transcription (SOCS2 and Bcl-2) of protective mediators, reduced neutrophil recruitment, and ameliorated intestinal damage and diarrhea severity in mice. In EGCs, TcdA and TcdB upregulated S100B-mediated IL-6 expression via activation of RAGE/PI3K/NFκB. Thus, CDI appears to upregulate colonic S100B signaling in EGCs, which in turn augment inflammatory response. Inhibition of S100B activity attenuates the intestinal injury and diarrhea caused by C. difficile toxins. Our findings provide new insight into the role of S100B in CDI pathogenesis and opens novel avenues for therapeutic interventions.
| S-EPMC8461106 | biostudies-literature
Project description:Complement-like proteins in arthropods defend against invading pathogens in the early phases of infection. Thioester-containing proteins (TEPs), which exhibit high similarity to mammalian complement C3, are thought to play a key role in the innate immunity of arthropods. We identified and characterized anti-dengue virus (DENV) host factors, in particular complement-like proteins, in the mosquito Aedes aegypti. Our results indicate that TEP1 limits DENV infection in Ae. aegypti. We showed that TEP1 transcription is highly induced in mosquitoes following DENV infection. Silencing TEP1 resulted in the up-regulation of viral RNA and proteins. In addition, the production of infectious virus particles increased in the absence of TEP1. We generated a transgenic mosquito line with a TEP1 loss-of-function phenotype under a blood meal-inducible promoter. We showed that viral protein and titers increased in transgenic mosquitoes after an infectious blood meal. Interestingly, expression of transcription factor Rel2 and certain anti-microbial peptides (AMPs) were inhibited in transgenic mosquitoes. Overall, our results suggest that TEP1 regulates the immune response and consequently controls the replication of dengue virus in mosquitoes. This finding provides new insight into the molecular mechanisms of mosquito host factors in the regulation of DENV replication.
| S-EPMC8155531 | biostudies-literature
Project description:As first responder cells in host defense, neutrophils must be carefully regulated to prevent collateral tissue injury. However, the intracellular events that titrate the neutrophil's response to inflammatory stimuli remain poorly understood. As a molecular switch, Ras activity is tightly regulated by Ras GTPase activating proteins (RasGAP) to maintain cellular active-inactive states. Here, we show that RASAL3, a RasGAP, is highly expressed in neutrophils and that its expression is upregulated by exogenous stimuli in neutrophils. RASAL3 deficiency triggers augmented neutrophil responses and enhanced immune activation in acute inflammatory conditions. Consequently, mice lacking RASAL3 (RASAL3-KO) demonstrate accelerated mortality in a septic shock model via induction of severe organ damage and hyperinflammatory response. The excessive neutrophilic hyperinflammation and increased mortality were recapitulated in a mouse model of sickle cell disease, which we found to have low neutrophil RASAL3 expression upon LPS activation. Thus, RASAL3 functions as a RasGAP that negatively regulates the cellular activity of neutrophils to modulate the inflammatory response. These results demonstrate that RASAL3 could serve as a therapeutic target to regulate excessive inflammation in sepsis and many inflammatory disease states.
| S-EPMC8579101 | biostudies-literature
Project description:Systemic bacterial infection is characterized by a robust whole-organism inflammatory response. Analysis of the immune response to infection involves technologies that typically focus on single organ systems and lack spatial information. Additionally, the analysis of individual inflammatory proteins requires antibodies specific to the protein of interest, limiting the panel of proteins that can be analyzed. Herein we describe the application of matrix-assisted laser desorption/ionization imaging mass spectrometry (MALDI IMS) to mice systemically infected with Staphylococcus aureus to identify inflammatory protein masses that respond to infection throughout an entire infected animal. Integrating the resolution afforded by magnetic resonance imaging (MRI) with the sensitivity of MALDI IMS provides three-dimensional spatially resolved information regarding the distribution of innate immune proteins during systemic infection, allowing comparisons to in vivo structural information and soft-tissue contrast via MRI. Thus, integrating MALDI IMS with MRI provides a systems-biology approach to study inflammation during infection.
| S-EPMC3377982 | biostudies-literature
Project description:BackgroundJian-Gan-Xiao-Zhi decoction (JGXZ), composed of Salvia miltiorrhiza Bunge, Panax notoginseng, Curcuma zedoaria, and other 9 types of herbs, has demonstrated beneficial effects on nonalcoholic fatty liver disease (NAFLD). However, the mechanisms behind JGXZ's impact on NAFLD remain unknown.MethodsIn this study, a NAFLD rat model induced by a high-fat diet (HFD) received oral treatment of JGXZ (8 or 16 g crude herb/kg) for 12 weeks. The therapeutic effects of JGXZ on NAFLD model rats were investigated through blood lipid levels and pathological liver changes. 16S rRNA analysis was used to study the changes in gut microbiota after JGXZ treatment. The expressions of occludin and tight junction protein 1 (ZO-1) in the colon were investigated using immunostaining to study the effects of JGXZ on gut permeability. The anti-inflammatory effects of JGXZ were also studied through measuring the levels of IL-1β, IL-6, and TNF-α in the serum and liver.ResultsJGXZ treatment could decrease body weight and ameliorate dyslipidemia in NAFLD model rats. H&E and Oil Red O staining indicated that JGXZ reduced steatosis and infiltration of inflammatory cells in the liver. 16S rRNA analysis showed that JGXZ impacted the diversity of gut microbiota, decreasing the Firmicutes-to-Bacteroidetes ratio, and increasing the relative abundance of probiotics, such as Alloprevotella, Lactobacillus, and Turicibacter. Gut permeability evaluation found that the expressions of ZO-1 and occludin in the colon were increased after JGXZ treatment. Moreover, JGXZ treatment could decrease the levels of IL-1β, IL-6, and TNF-α in the serum and liver.ConclusionsOur study illustrated that JGXZ could ameliorate NAFLD through modulating gut microbiota, decreasing gut permeability, and alleviating inflammatory response.
| S-EPMC8007356 | biostudies-literature