RESUMEN

Alcohol use is associated with an increased incidence of negative health outcomes in burn patients due to biological mechanisms that include a dysregulated inflammatory response and increased intestinal permeability. This study used phosphatidylethanol (PEth) in blood, a direct biomarker of recent alcohol use, to investigate associations between a recent history of alcohol use and the fecal microbiota, short chain fatty acids, and inflammatory markers in the first week after a burn injury for nineteen participants. Burn patients were grouped according to PEth levels of low or high and differences in the overall fecal microbial community were observed between these cohorts. Two genera that contributed to the differences and had higher relative abundance in the low PEth burn patient group were Akkermansia, a mucin degrading bacteria that improves intestinal barrier function, and Bacteroides, a potentially anti-inflammatory bacteria. There was no statistically significant difference between levels of short chain fatty acids or intestinal permeability across the two groups. To our knowledge, this study represents the first report to evaluate the effects of burn injury and recent alcohol use on early post burn microbiota dysbiosis, inflammatory response, and levels of short chain fatty acids. Future studies in this field are warranted to better understand the factors associated with negative health outcomes and develop interventional trials.

Asunto(s)

RESUMEN

Burn-injured patients with alcohol use disorder (AUD) have increased morbidity and mortality compared to alcohol-abstaining individuals with similar injuries. It is hypothesized that this is due, in part, to alcohol-induced dysregulation of the systemic inflammatory response, leading to worsened clinical outcomes, including increased susceptibility to infection, and heightened cognitive impairment. To examine the effects of alcohol on inflammatory markers after burn injury, we used multiplex assays to measure a panel of 48 cytokines, chemokines, and growth factors in the plasma of burn patents within 24 h of admission to the University of Colorado Burn Center. Thirty patients were enrolled between July 2018 to February 2020 and were stratified based on presence of AUD and total body surface area (TBSA) burn of ≥20% into four groups: [AUD-, TBSA <20%, N = 12], [AUD+, TBSA <20%, N = 3], [AUD-, TBSA ≥20%, N = 8], [AUD+, TBSA ≥20%, N = 7]. In addition, Confusion Assessment Method (CAM) scores were collected to evaluate patient delirium during the course of hospitalization. Multivariate statistical analysis demonstrated a number of cytokines and other factors that were significantly different between the groups. For example, the anti-inflammatory cytokine interleukin 1 receptor antagonist (IL-1ra) was dampened in the AUD+, TBSA ≥20% cohort with a 75.2% decrease compared to AUD-, TBSA ≥20%, and an 83.9% decrease compared to AUD-, TBSA <20% (p = 0.008). Additionally, plasma levels of the pro-inflammatory mediator CXCL12 (C-X-C motif chemokine ligand 12, also known as stromal cell-derived factor 1, SDF-1) was higher in the AUD + groups (p = 0.03) and similarly, IL-18 levels were greater in AUD+, TBSA ≥20% (p = 0.009). Eotaxin (also known as cytokine CC motif ligand 11, CCL11) was markedly elevated in the AUD+, TBSA ≥20% cohort with a 2.4-fold increase over the AUD-, TBSA ≥20%, and a 1.7-fold rise compared to the AUD-, TBSA <20% cohorts (p = 0.04). Interestingly, there was also a marked rise in CAM + delirium scores (85.7%) among the AUD + patients with TBSA ≥20% (p = 0.02). Not surprisingly, we found that hospital stays increased with AUD+ and larger burns (p = 0.0009). Our findings reveal that burn patients who misuse alcohol have aberrant inflammatory responses that may lead to greater immune dysregulation and worse clinical outcomes.

Asunto(s)

RESUMEN

The gastrointestinal (GI) tract is a vitally important site for the adsorption of nutrients as well as the education of immune cells. Homeostasis of the gut is maintained by the interplay of the intestinal epithelium, immune cells, luminal Ags, and the intestinal microbiota. The well-being of the gut is intrinsically linked to the overall health of the host, and perturbations to this homeostasis can have severe impacts on local and systemic health. One factor that causes disruptions in gut homeostasis is age, and recent research has elucidated how critical systems within the gut are altered during the aging process. Intestinal stem cell proliferation, epithelial barrier function, the gut microbiota, and the composition of innate and adaptive immune responses are all altered in advanced age. The aging population continues to expand worldwide, a phenomenon referred to as the "Silver Tsunami," and every effort must be made to understand how best to prevent and treat age-related maladies. Here, recent research about changes observed in the intestinal epithelium, the intestinal immune system, the microbiota, and how the aging gut interacts with and influences other organs such as the liver, lung, and brain are reviewed. Better understanding of these age-related changes and their impact on multi-organ interactions will aid the development of therapies to increase the quality of life for all aged individuals.

Asunto(s)

RESUMEN

Cell adhesion and detachment to and from the extracellular matrix (ECM) are critical regulators of cell function and fate due to the exchange of mechanical signals between the cell and its microenvironment. To study this cell mechanobiology, researchers have developed several innovative methods to investigate cell adhesion in vitro; however, most of these culture platforms are unnaturally stiff or static. To better capture the soft, dynamic nature of the ECM, we present a PEG-based hydrogel in which the context and geometry of the extracellular space can be precisely controlled in situ via two-photon induced erosion. Here, we characterize the two-photon erosion process, demonstrate its efficacy in the presence of cells, and subsequently exploit it to induce subcellular detachment from soft hydrogels. A working space was established for a range of laser powers required to induce complete erosion of the gel, and these data are plotted with model predictions. From this working space, two-photon irradiation parameters were selected for complete erosion in the presence of cells. Micron-scale features were eroded on and within a gel to demonstrate the resolution of patterning with these irradiation conditions. Lastly, two-photon irradiation was used to erode the material at the cell-gel interface to remove cell adhesion sites selectively, and cell retraction was monitored to quantify the mesenchymal stem cell (MSC) response to subcellular detachment from soft materials.