IU Indianapolis ScholarWorks :: Browsing by Author "Drucker, Natalie A."

Browsing by Author "Drucker, Natalie A."

Now showing 1 - 10 of 29

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.
The Assessment of Microbiome Changes and Fecal Volatile Organic Compounds during Experimental Necrotizing Enterocolitis
(Elsevier, 2021) Hosfield, Brian D.; Drucker, Natalie A.; Pecoraro, Anthony R.; Shelley, William C.; Li, Hongge; Baxter, Nielson T.; Hawkins, Troy B.; Markel, Troy A.; Surgery, School of Medicine
Introduction: Necrotizing enterocolitis (NEC) remains a devastating disease that affects the gastrointestinal tract of the preterm infant. Volatile organic compounds (VOCs) have emerged as a non-invasive biomarker in many diseases. We hypothesized that fecal VOC profiles would be significantly different between control and NEC pups in a NEC mouse model. Methods: Experimental NEC was induced in five-day-old mice. Breastfed and formula-fed control groups were also studied. After four days, pups were euthanized and intestines were H&E stained and blindly scored. Stool microbiome analysis was performed via 16S rRNA sequencing. VOC analysis was assessed by the CyranoseⓇ 320 eNose device and p<0.05 was significant. Results: NEC pups had severe intestinal injury when compared to controls. Microbiome analysis showed that both control groups had significantly higher microbial diversity and relative abundance of Lactobacillus than NEC, and lower relative abundance of Escherichia. Fecal VOC profile for NEC pups was significantly different from controls. Conclusions: Experimental NEC was associated with intestinal dysbiosis. Fecal VOC analysis by the CyranoseⓇ 320 eNose device can discriminate NEC pups from both breastfed and formula-fed controls. Further research is warranted to establish whether fecal VOCs can be used as a biomarker or predictive algorithm to diagnose NEC.
Cryopreserved Homografts in Infected Infrainguinal Fields Are Associated with Frequent Reinterventions and Poor Amputation-Free Survival
(Elsevier, 2018) Wang, S. Keisin; Gutwein, Ashley R.; Drucker, Natalie A.; Murphy, Michael P.; Fajardo, Andres; Dalsing, Michael C.; Motaganahalli, Raghu L.; Lemmon, Gary W.; Surgery, School of Medicine
Background Single-length saphenous vein continues to be the conduit of choice in infected-field critical limb ischemia. However, half of these individuals have inadequate vein secondary to previous use or chronic venous disease. We reviewed our outcomes of infected-field infrainguinal bypasses performed with cryopreserved homografts (CHs), a widely accepted alternative to autogenous vein in this setting. Methods This is a retrospective, institutional descriptive analysis of infected-field infrainguinal revascularizations between 2012 and 2015. Results Twenty-four operations were performed in the same number of patients for limb ischemia with signs of active infection. The mean age of the cohort examined was 62.5 ± 14.4 (standard deviation) years. Mean Society of Vascular Surgery risk score was 3.9 with a baseline Rutherford's chronic ischemia score of 4.3 at presentation. Emergent procedures constituted 29% of cases, and the remainder cases were urgent procedures. The CH bypass captured was a reoperative procedure in all but one of the patients. Culture positivity was present in 75% of cases with Staphylococcus aureus (29%), the most commonly isolated organism. Thirty-day mortality and major adverse cardiovascular events were both 4%. Amputation-free survival (AFS) was 75% at 30 days. Similarly, 30-day reintervention was 38% with debridement (43%) and bleeding (29%), the most common indications. Average duration of follow-up was 27.9 ± 20.4 months (range: 0.5–60.4). Mean length of stay was 14.8 days. Reinfection requiring an additional procedure or antibiotic regimen separate from the index antibiotic course was 13%. Primary patency and AFS at 1 year was 50% and 58%, respectively. Primary patency and AFS at 2 years was 38% and 52%, respectively. Limb salvage at 1 and 2 years was 70% and 65%, respectively. Fifteen patients (63%) required reintervention during the follow-up period with 40% of those subjects undergoing multiple procedures. Conclusions CHs remain a marginal salvage conduit in the setting of infection and no autogenous choices. Therefore, clinicians should individualize usage of this high-cost product in highly selected patients only.
Description of human AAA by cytokine and immune cell aberrations compared to risk-factor matched controls
(Elsevier, 2018-08) Wang, S. Keisin; Green, Linden A.; Gutwein, Ashley R.; Drucker, Natalie A.; Motaganahalli, Raghu L.; Gupta, Alok K.; Fajardo, Andres; Murphy, Michael P.; Surgery, School of Medicine
BACKGROUND: The pathogenesis driving the formation of abdominal aortic aneurysms continues to be poorly understood. Therefore, we systemically define the cytokine and circulating immune cell environment observed in human abdominal aortic aneurysm compared with risk-factor matched controls. METHODS: From 2015 to 2017, a total of 274 patients donated blood to the Indiana University Center for Aortic Disease. Absolute concentrations of circulating cytokines were determined, using enzyme-linked immunosorbent assays while the expression of circulating immune cell phenotypes were assayed via flow cytometric analysis. RESULTS: Human abdominal aortic aneurysm is characterized by a significant depletion of the antigen-specific, CD4+ Tr1 regulatory lymphocyte that corresponds to an upregulation of the antigen-specific, inflammatory Th17 cell. We found no differences in the incidence of Treg, B10, and myeloid-derived suppressor regulatory cells. Similarly, no disparities were noted in the following inflammatory cytokines: IL-1β, C-reactive protein, tumor necrosis factor α, interferon γ, and IL-23. However, significant upregulation of the inflammatory cytokines osteopontin, IL-6, and IL-17 were noted. Additionally, no changes were observed in the regulatory cytokines IL-2, IL-4, IL-13, TNF-stimulated gene 6 protein, and prostaglandin E2, but we did observe a significant decrease in the essential regulatory cytokine IL-10. CONCLUSION: In this investigation, we systematically characterize the abdominal aortic aneurysm-immune environment and present preliminary evidence that faulty immune regulation may also contribute to aneurysm formation and growth.
Diagnosis and management of the venous malformations of Klippel-Trénaunay syndrome
(Elsevier, 2017-07) Wang, S. Keisin; Drucker, Natalie A.; Gupta, Alok K.; Marshalleck, Francis E.; Dalsing, Michael C.; Surgery, School of Medicine
Objective A dearth of information exists in the literature regarding current practice in the management of Klippel-Trénaunay syndrome (KTS), a rare condition. We review and describe the etiology, diagnosis, and treatment of KTS. Methods Relevant data were synthesized from a Medline review using a combination of the keyterms “Klippel” and “Trénaunay.” The majority of hits described singular case reports and were subsequently excluded. The remaining papers were then reviewed and included on the basis of the quality of evidence and the authors' discretion. Conclusions KTS is characterized by a clinical triad of extremity varicosities, cutaneous vascular malformations, and hypertrophy of soft tissues and long bones. The diagnosis is clinically supplemented with magnetic resonance imaging and computed tomography. Although this syndrome is associated with significant comorbidities, such as pain, edema, ulcerations, and pruritus, it is rarely the cause of death. The backbone of treatment is nonoperative in nature but should be supplemented with minimally invasive, endovascular, and rarely open surgical procedures for refractory cases.
Direct Peritoneal Resuscitation Improves Mesenteric Perfusion by Nitric Oxide Dependent Pathways
(Elsevier, 2017-06) Khaneki, Sina; Jensen, Amanda R.; Drucker, Natalie A.; Markel, Troy A.; Department of Surgery, IU School of Medicine
Background Direct peritoneal resuscitation (DPR) has been shown to increase survival after intestinal ischemia and reperfusion injury (I/R). We have previously appreciated that minimum essential medium (MEM), a synthetic cell culture medium with bovine serum, glutamine, and antibiotics, contributes to these benefits. We hypothesized that (1) DPR using MEM as a dialysate would increase mesenteric perfusion, improve intestinal mucosal injury, and limit intestinal and hepatic inflammation after intestinal I/R and (2) these improvements would be dependent on endothelial nitric oxide pathways. Methods Eight-week-old C57Bl6J wild-type (WT) and eNOS Knock Out (eNOS KO) male mice were anesthetized and intestinal ischemia was induced for 60 min. After ischemia, 1 mL of phosphate buffered saline vehicle or MEM was injected into the abdominal cavity. Intestinal perfusion was reassessed after 48 h. Animals were then euthanized, and intestines and livers explanted for histologic and molecular analyses. Results DPR with MEM significantly improved mesenteric perfusion compared with vehicle (phosphate buffered saline) as measured by Laser Doppler Imaging (WT + MEM 91.58 ± 13.74%, WT + Vehicle 44.27 ± 11.93%, P < 0.05); however, these benefits were lost when endothelial nitric oxide signaling pathways were ablated (eNOS KO + MEM 21.72 ± 5.67 %, eNOS KO + Vehicle 45.24± 11.31%). WT mice treated with MEM also had significantly better preservation of their mucosal architecture (WT + MEM Mdn = 1.0, interquartile range [IQR] = 1.25, WT + Vehicle Mdn = 3.0, IQR = 2.0, P < 0.05). When we compared eNOS KO mice treated with either MEM or vehicle the protective effect of MEM disappeared (eNOS KO + MEM Mdn = 2.0, IQR = 2.25, eNOS KO + Vehicle Mdn = 2.0, IQR = 1.0 P > 0.05). Intestinal levels of interleukin (IL)-1β were increased in WT animals treated with MEM compared with eNOS KOs, whereas concentrations of intestinal IL-6 were similar between groups. Hepatic levels of both IL-1β and IL-6 were significantly elevated in eNOS KOs compared with WT treated with MEM. Conclusions DPR with MEM has significant therapeutic potential for improving mesenteric perfusion, intestinal injury, and the local inflammatory response after intestinal I/R. These benefits appear to be dependent on nitric oxide signaling within the endothelium.
Gastric pneumatosis: An unusual presentation of superior mesenteric artery syndrome
(Elsevier, 2018-09-01) Drucker, Natalie A.; Marine, Megan B.; Rescorla, Frederick J.; Surgery, School of Medicine
We present a case of extensive gastric pneumatosis with portal venous air due to superior mesenteric artery syndrome in an underweight, developmentally normal seventeen-year-old boy. Despite his alarming imaging findings, his abdominal exam was benign and he was successfully treated nonoperatively.
Harvest Tissue Source Does Not Alter the Protective Power of Stromal Cell Therapy Following Intestinal Ischemia and Reperfusion Injury
(Elsevier, 2016-08) Jensen, Amanda R.; Manning, Morenci M.; Khaneki, Sina; Drucker, Natalie A.; Markel, Troy A.; Medicine, School of Medicine
Background Transplantation of mesenchymal stromal cells (MSCs) may be a novel treatment for intestinal ischemia. The optimal stromal cell source that could yield maximal protection following injury, however, has not been identified. We hypothesized that: 1) MSCs would increase survival and mesenteric perfusion, preserve intestinal histological architecture, and limit inflammation following intestinal ischemia and reperfusion injury (I/R), and 2) MSCs harvested from different sources of tissue would have equivalent protective properties to the intestine following I/R. Methods Adult male mice were anesthetized and a midline laparotomy performed. The intestines were eviscerated, the small bowel mesenteric root identified, and baseline intestinal perfusion was determined using Laser Doppler Imaging (LDI). Intestinal ischemia was established by temporarily occluding the superior mesenteric artery for 60 minutes with a non-crushing clamp. Following ischemia, the clamp was removed and the intestines were allowed to recover. Prior to abdominal closure, 2 × 106 human umbilical (USCs), bone-marrow (BMSCs) derived MSCs, or keratinocytes in 250μl of phosphate-buffered saline (PBS) vehicle were injected into the peritoneum. Animals were allowed to recover for 12 or 24 hours (perfusion, histology, inflammatory studies), or 7 days (survival studies). Survival data was analyzed using log rank test. Perfusion was expressed as percentage of baseline and 12 and 24 hour data was analyzed using one way ANOVA and student’s t-test. Non parametric data was compared using Mann-Whitney-U test. A p-value of less than 0.05 was significant. Results All MSCs increased seven day survival following I/R and were superior to vehicle or keratinocytes (P<0.05). All MSCs increased mesenteric perfusion above vehicle at 12 and 24 hours following injury (P<0.05). All MSCs provided superior perfusion compared to keratinocytes at 24 hours post-injury (P<0.05). Administration of each MSC line improved intestinal histology after I/R (P<0.05). Multiple pro-inflammatory chemokines were down-regulated following application of MSCs suggesting a decreased inflammatory response following MSC therapy. Conclusion Transplantation of MSCs following intestinal I/R, irrespective of source tissue, significantly increases survival and mesenteric perfusion while limiting intestinal damage and inflammation. Further studies are needed to identify the mechanism that these cells utilize to promote improved outcomes following injury.
Human Mesenchymal Stem Cell Hydrogen Sulfide Production Critically Impacts the Release of Other Paracrine Mediators Following Injury
(Elsevier, 2020-10) Markel, Troy A.; Drucker, Natalie A.; Jensen, Amanda R.; Olson, Kenneth R.; Surgery, School of Medicine
Background: The use of mesenchymal stem cells (MSCs) for treatment during ischemia is novel. Hydrogen sulfide (H2S) is an important paracrine mediator that is released from MSCs to facilitate angiogenesis and vasodilation. Three enzymes, cystathionine-beta-synthase (CBS), cystathionine-gamma-lyase (CSE), and 3-mercaptopyruvate-sulfurtransferase (MPST), are mainly responsible for H2S production. However, it is unclear how these enzymes impact the production of other critical growth factors and chemokines. We hypothesized that the enzymes responsible for H2S production in human MSCs would also critically regulate other growth factors and chemokines. Materials and methods: Human MSCs were transfected with CBS, MPST, CSE, or negative control small interfering RNA. Knockdown of enzymes was confirmed by polymerase chain reaction. Cells were plated in 12-well plates at 100,000 cells per well and stimulated with tumor necrosis factor-α (TNF-α; 50 ng/mL), lipopolysaccharide (LPS; 200 ng/mL), or 5% hypoxia for 24 h. Supernatants were collected, and cytokines measured by multiplex beaded assay. Data were compared with the Mann-Whitney U-test, and P < 0.05 was significant. Results: TNF-α, LPS, and hypoxia effectively stimulated MSCs. Granulocyte colony-stimulating factor (GCSF), epidermal growth factor, fibroblast growth factor, granulocyte/monocyte colony-stimulating factor (GMCSF), vascular endothelial growth factor, and interferon gamma-inducible protein 10 were all significantly elevated when CSE was knocked down during TNF-α stimulation (P < 0.05). Knockdown of MPST during LPS stimulation more readily increased GCSF and epidermal growth factor but decreased GMCSF (P < 0.05). CBS knockdown decreased production of GCSF, fibroblast growth factor, GMCSF, and vascular endothelial growth factor (P < 0.05) after hypoxia. Conclusions: The enzymes that produce H2S in MSCs are also responsible for the production of other stem cell paracrine mediators under stressful stimuli. Therefore, reprogramming MSCs to endogenously produce more H2S as a therapeutic intervention could also critically impact other paracrine mediators, which may alter the desired beneficial effects.
Hydrogen Sulfide Donor GYY4137 Acts Through Endothelial Nitric Oxide to Protect Intestine in Murine Models of Necrotizing Enterocolitis and Intestinal Ischemia
(Elsevier, 2019-02) Drucker, Natalie A.; Jensen, Amanda R.; Te Winkel, Pieter Jan; Markel, Troy A.; Surgery, School of Medicine
BACKGROUND: Necrotizing enterocolitis (NEC) in premature infants is often a devastating surgical condition with poor outcomes. GYY4137 is a long-acting donor of hydrogen sulfide, a gasotransmitter that is protective against intestinal injury in experimental NEC, likely through protection against injury secondary to ischemia. We hypothesized that administration of GYY4137 would improve mesenteric perfusion, reduce intestinal injury, and reduce inflammatory responses in experimental NEC and ischemia-reperfusion injury, and that these benefits would be mediated through endothelial nitric oxide synthase-dependent pathways. METHODS: NEC was induced in C57BL/6 wild-type (WT) and endothelial nitric oxide synthase (eNOS) knockout (eNOSKO) pups via maternal separation, formula feeding, enteral lipopolysaccharide, and intermittent hypoxic and hypothermic stress. Pups received daily intraperitoneal injections of 50 mg/kg GYY4137 or phosphate buffered saline vehicle. In separate groups, adult male WT and eNOSKO mice underwent superior mesenteric artery occlusion for 60 min. Before abdominal closure, 50 mg/kg GYY4137 or phosphate buffered saline vehicle was administered into the peritoneal cavity. Laser doppler imaging was used to assess mesenteric perfusion of pups at baseline and on postnatal day 9, and the adult mice at baseline and 24 h after ischemic insult. After euthanasia, the terminal ileum of each animal was fixed, paraffin embedded, sectioned, and stained with hematoxylin and eosin. Sections were blindly graded using published injury scores. Intestinal tissue was homogenized and cytokines measured by ELISA. Data were compared using Mann-Whitney U test, and P-values <0.05 were significant. RESULTS: After NEC and ischemia reperfusion (I/R) injury, GYY4137 improved perfusion in WT mice compared to vehicle, but this effect was lost in the eNOSKO animals. Histologic injury followed a similar pattern with reduced intestinal injury in WT mice treated with GYY4137, and no significant improvement in the eNOSKO group. Cytokine expression after GYY4137 administration was altered by the ablation of eNOS in both NEC and I/R injury groups, with significant differences noted in Interleukin 6 and vascular endothelial growth factor. CONCLUSIONS: GYY4137, a long-acting donor of hydrogen sulfide, has potential as a therapeutic compound for NEC. It improves mesenteric perfusion and intestinal injury in experimental NEC and intestinal I/R injury, and these benefits appear to be mediated through eNOS-dependent pathways.

Browsing by Author "Drucker, Natalie A."

Results Per Page

Sort Options