Browsing by Author "Hunter, Chelsea E."

Now showing 1 - 5 of 5
  • Thumbnail Image
    Item
    A hydrogen-sulfide derivative of mesalamine reduces the severity of intestinal and lung injury in necrotizing enterocolitis through endothelial nitric oxide synthase
    (American Physiological Society, 2022-10-01) Hosfield, Brian D.; Hunter, Chelsea E.; Li, Hongge; Drucker, Natalie A.; Pecoraro, Anthony R.; Manohar, Krishna; Shelley, W. Christopher; Markel, Troy A.; Surgery, School of Medicine
    Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and 4) NEC + 130 mg/kg ATB-429. Mesalamine and ATB-429 doses were equimolar. Pups were monitored for sickness scores and perfusion to the gut was measured by Laser Doppler Imaging (LDI). After euthanasia of the pups, intestine and lung were hematoxylin and eosin-stained and scored for injury in a blind fashion. TLR4 expression was quantified by Western blot and IL-6 expression by ELISA. P < 0.05 was significant. Both WT and eNOSKO breastfed controls underwent normal development and demonstrated milder intestinal and pulmonary injury compared with NEC groups. For the WT groups, ATB-429 significantly improved weight gain, reduced clinical sickness score, and improved perfusion compared with the NEC group. In addition, WT ATB-429 pups had a significantly milder intestinal and pulmonary histologic injury when compared with NEC. ATB-429 attenuated the increase in TLR4 and IL-6 expression in the intestine. When the experiment was repeated in eNOSKO pups, ATB-429 offered no benefit in weight gain, sickness scores, perfusion, intestinal injury, pulmonary injury, or decreasing intestinal inflammatory markers. An H2S derivative of mesalamine improves outcomes in experimental NEC. Protective effects appear to be mediated through eNOS. Further research is warranted to explore whether ATB-429 may be an effective oral therapy to combat NEC.
  • Thumbnail Image
    Item
    Hydrogen Sulfide Improves Outcomes in a Murine Model of Necrotizing Enterocolitis via the Cys440 Residue on Endothelial Nitric Oxide Synthase
    (Elsevier, 2023) Hunter, Chelsea E.; Mesfin, Fikir M.; Manohar, Krishna; Liu, Jianyun; Shelley, W. Christopher; Brokaw, John P.; Pecoraro, Anthony R.; Hosfield, Brian D.; Markel, Troy A.; Surgery, School of Medicine
    Background: Hydrogen sulfide (H2S) has been shown to improve outcomes in a murine model of necrotizing enterocolitis (NEC). There is evidence in humans that H2S relies on endothelial nitric oxide synthase (eNOS) to exert its protective effects, potentially through the persulfidation of eNOS at the Cysteine 443 residue. We obtained a novel mouse strain with a mutation at this residue (eNOSC440G) and hypothesized that this locus would be critical for GYY4137 (an H2S donor) to exert its protective effects. Methods: Necrotizing enterocolitis was induced in 5-day old wild type (WT) and eNOSC440G mice using intermittent exposure to hypoxia and hypothermia in addition to gavage formula feeds. On postnatal day 9, mice were humanely euthanized. Data collected included daily weights, clinical sickness scores, histologic lung injury, intestinal injury (macroscopically and histologically), and intestinal perfusion. During the NEC model, pups received daily intraperitoneal injections of either GYY4137 (50 mg/kg) or PBS (vehicle). Data were tested for normality and compared using t-test or Mann-Whitney, and a p-value <0.05 was considered significant. Results: In WT mice, the administration of GYY4137 significantly improved clinical sickness scores, attenuated intestinal and lung injury, and improved mesenteric perfusion compared to vehicle (p < 0.05). In eNOSC440G mice, the treatment and vehicle groups had similar clinical sickness scores, intestinal and lung injury scores, and intestinal perfusion. Conclusions: GYY4137 administration improves clinical outcomes, attenuates intestinal and lung injury, and improves perfusion in a murine model of necrotizing enterocolitis. The beneficial effects of GYY4137 are dependent on the Cys440 residue of eNOS.
  • Thumbnail Image
    Item
    Inter- and Intra-rater Reliability of A Grading System for Congenital Diaphragmatic Hernia Defect Size
    (Elsevier, 2019-01) Hunter, Chelsea E.; Saenz, Zoe M.; Nunez, Daisy; Timsina, Lava; Gray, Brian W.; Surgery, School of Medicine
    Background The Congenital Diaphragmatic Hernia Study Group (CDHSG) registry is a multi-institutional tool to track outcomes of patients with CDH. The CDHSG asks surgeons to categorize diaphragmatic defect sizes as type A-D based on published guidelines. The reported size of the defect has been correlated with patient outcomes, but the reliability of this system has never been studied. Our goal was to evaluate the inter- and intra-rater reliability of the CDHSG grading system. Materials and methods Forty-six operative notes from CDH patients that underwent surgical repair at a single institution were collected and cropped to include only the information necessary to grade the hernia defect based on the CDHSG guidelines. The defects were graded by nine pediatric surgeons on two separate occasions (18 wk apart). Inter-rater reliability was calculated using a Cohen's kappa (κ). Intra-rater reliability was calculated using an intraclass correlation coefficient. Results Inter-rater reliability was minimal to weak (κ round1 = 0.395, κ round2 = 0.424). Agreement ranged from 19.57% (κ = −0.0745) to 82.61% (κ = 0.7543). Inter-rater agreement was similar despite operative findings and outcomes: survival yes/no (κ = 0.3690, κ = 0.3518), need for ECMO yes/no (κ = 0.3323, κ = 0.3362), patch repair yes/no (κ = 0.2050, κ = 0.1916), and liver up/down (κ = 0.2941, κ = 0.4404). Intra-rater reliability was good to excellent (intraclass correlation coefficient = 0.88, 95% CI [0.83-0.92]). Agreement with oneself ranged from 71.74% to 93.48%. Conclusions The demonstrated weak inter-rater reliability of the current CDHSG grading system shows the need for improvement in how the grading system is applied by surgeons when reporting CDH defect size.
  • Thumbnail Image
    Item
    Recent Development of the Molecular and Cellular Mechanisms of Hydrogen Sulfide Gasotransmitter
    (MDPI, 2022-09-10) Liu, Jianyun; Mesfin, Fikir M.; Hunter, Chelsea E.; Olson, Kenneth R.; Shelley, W. Christopher; Brokaw, John P.; Manohar, Krishna; Markel, Troy A.; Surgery, School of Medicine
    Hydrogen sulfide has been recently identified as the third biological gasotransmitter, along with the more well studied nitric oxide (NO) and carbon monoxide (CO). Intensive studies on its potential as a therapeutic agent for cardiovascular, inflammatory, infectious and neuropathological diseases have been undertaken. Here we review the possible direct targets of H2S in mammals. H2S directly interacts with reactive oxygen/nitrogen species and is involved in redox signaling. H2S also reacts with hemeproteins and modulates metal-containing complexes. Once being oxidized, H2S can persulfidate proteins by adding -SSH to the amino acid cysteine. These direct modifications by H2S have significant impact on cell structure and many cellular functions, such as tight junctions, autophagy, apoptosis, vesicle trafficking, cell signaling, epigenetics and inflammasomes. Therefore, we conclude that H2S is involved in many important cellular and physiological processes. Compounds that donate H2S to biological systems can be developed as therapeutics for different diseases.
  • Thumbnail Image
    Item
    Stem cell derived therapies to preserve and repair the developing intestine
    (Elsevier, 2023) Mesfin, Fikir M.; Manohar, Krishna; Hunter, Chelsea E.; Shelley, W. Christopher; Brokaw, John P.; Liu, Jianyun; Ma, Minglin; Markel, Troy A.; Surgery, School of Medicine
    Stem cell research and the use of stem cells in therapy have seen tremendous growth in the last two decades. Neonatal intestinal disorders such as necrotizing enterocolitis, Hirschsprung disease, and gastroschisis have high morbidity and mortality and limited treatment options with varying success rates. Stem cells have been used in several pre-clinical studies to address various neonatal disorders with promising results. Stem cell and patient population selection, timing of therapy, as well as safety and quality control are some of the challenges that must be addressed prior to the widespread clinical application of stem cells. Further research and technological advances such as the use of cell delivery technology can address these challenges and allow for continued progress towards clinical translation.