Kathryn Burge

University of Oklahoma Health Sciences Center

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Hala Chaaban

University of Oklahoma Health Sciences Center

Jeffrey Eckert

University of Oklahoma Health Sciences Center

Adam Wilson

University of Oklahoma Health Sciences Center

Sampath Parthasarathy

University of Central Florida

Chandrakala Aluganti Narasimhulu

University of Central Florida

Aarthi Gunasekaran

University of Oklahoma Health Sciences Center

Steven J. McElroy

Eunice Kennedy Shriver National Institute of Child Health and Human Development

Krithika Selvarajan

University of Central Florida

Florea Lupu

Oklahoma Medical Research Foundation

Dmitry Litvinov

All-Russian Scientific Research Institute of Food Biotechnology

Cooperative Institutions

University of Oklahoma Health Sciences Center

University of Oklahoma

Oklahoma Medical Research Foundation

Oklahoma City University

University of Central Florida

OU Health

Children's Hospital of Oklahoma

The Ohio State University

The Ohio State University Wexner Medical Center

The University of Texas Southwestern Medical Center

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Endothelial RIPK3 minimizes organotypic inflammation and vascular permeability in ischemia-reperfusion injury

bioRxiv (Cold Spring Harbor Laboratory) (2024)

Charmain F. Johnson Christopher M. Schafer Kathryn Burge Brian G. Coon Hala Chaaban

ABSTRACT Recent studies have revealed a link between endothelial receptor-interacting protein kinase 3 (RIPK3) and vascular integrity. During mouse embryonic development, hypoxia can trigger elevated endothelial RIPK3 that contributes to lethal vascular rupture. However, it is unknown whether RIPK3 regulate endothelial barrier function in adult vasculature under hypoxic injury conditions such as ischemia-reperfusion (I/R) injury. Here we performed inducible genetic deletion of endothelial Ripk3 ( Ripk iECKO ) in mice, which led to elevated vascular permeability in the small intestine and multiple distal organs after intestinal I/R injury. Mechanistically, this vascular permeability correlated with increased endothelial secretion of IL-6 and organ-specific expression of VCAM-1 and ICAM-1 adhesion molecules. Circulating monocyte depletion with clodronate liposomes reduced permeability in organs with elevated adhesion molecules, highlighting the contribution of monocyte adhesion and extravasation to Ripk iECKO barrier dysfunction. These results elucidate mechanisms by which RIPK3 regulates endothelial inflammation to minimize vascular permeability in I/R injury. GRAPHICAL ABSTRACT

Vascular permeability

Extravasation

10.1101/2024.11.25.625188

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Curcumin and Intestinal Inflammatory Diseases: Molecular Mechanisms of Protection

International Journal of Molecular Sciences (2019)

Kathryn Burge Aarthi Gunasekaran Jeffrey Eckert Hala Chaaban

Intestinal inflammatory diseases, such as Crohn’s disease, ulcerative colitis, and necrotizing enterocolitis, are becoming increasingly prevalent. While knowledge of the pathogenesis of these related diseases is currently incomplete, each of these conditions is thought to involve a dysfunctional, or overstated, host immunological response to both bacteria and dietary antigens, resulting in unchecked intestinal inflammation and, often, alterations in the intestinal microbiome. This inflammation can result in an impaired intestinal barrier allowing for bacterial translocation, potentially resulting in systemic inflammation and, in severe cases, sepsis. Chronic inflammation of this nature, in the case of inflammatory bowel disease, can even spur cancer growth in the longer-term. Recent research has indicated certain natural products with anti-inflammatory properties, such as curcumin, can help tame the inflammation involved in intestinal inflammatory diseases, thus improving intestinal barrier function, and potentially, clinical outcomes. In this review, we explore the potential therapeutic properties of curcumin on intestinal inflammatory diseases, including its antimicrobial and immunomodulatory properties, as well as its potential to alter the intestinal microbiome. Curcumin may play a significant role in intestinal inflammatory disease treatment in the future, particularly as an adjuvant therapy.

Enterocolitis

Pathogenesis

10.3390/ijms20081912

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Citations (131)

<em>In Vitro </em>Apical-Out Enteroid Model of Necrotizing Enterocolitis

Journal of Visualized Experiments (2022)

Kathryn Burge Adam Wilson Hala Chaaban

Necrotizing enterocolitis (NEC) is a devastating disease affecting preterm infants, characterized by intestinal inflammation and necrosis. Enteroids have recently emerged as a promising system to model gastrointestinal pathologies. However, currently utilized methods for enteroid manipulation either lack access to the apical surface of the epithelium (three-dimensional [3D]) or are time-consuming and resource-intensive (two-dimensional [2D] monolayers). These methods often require additional steps, such as microinjection, for the model to become physiologically translatable. Here, we describe a physiologically relevant and inexpensive protocol for studying NEC in vitro by reversing enteroid polarity, resulting in the apical surface facing outward (apical-out). An immunofluorescent staining protocol to examine enteroid barrier integrity and junctional protein expression following exposure to tumor necrosis factor-alpha (TNF-α) or lipopolysaccharide (LPS) under normoxic or hypoxic conditions is also provided. The viability of 3D apical-out enteroids exposed to normoxic or hypoxic LPS or TNF-α for 24 h is also evaluated. Enteroids exposed to either LPS or TNF-α, in combination with hypoxia, exhibited disruption of epithelial architecture, a loss of adherens junction protein expression, and a reduction in cell viability. This protocol describes a new apical-out NEC-in-a-dish model which presents a physiologically relevant and cost-effective platform to identify potential epithelial targets for NEC therapies and study the preterm intestinal response to therapeutics.

Necrotizing Enterocolitis

Adherens junction

Viability assay

10.3791/64003

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Acceleration of Small Intestine Development and Remodeling of the Microbiome Following Hyaluronan 35 kDa Treatment in Neonatal Mice

Nutrients (2021)

Hala Chaaban Kathryn Burge Jeffrey Eckert MaJoi Trammell David W. Dyer

The beneficial effects of human milk suppressing the development of intestinal pathologies such as necrotizing enterocolitis in preterm infants are widely known. Human milk (HM) is rich in a multitude of bioactive factors that play major roles in promoting postnatal maturation, differentiation, and the development of the microbiome. Previous studies showed that HM is rich in hyaluronan (HA) especially in colostrum and early milk. This study aims to determine the role of HA 35 KDa, a HM HA mimic, on intestinal proliferation, differentiation, and the development of the intestinal microbiome. We show that oral HA 35 KDa supplementation for 7 days in mouse pups leads to increased villus length and crypt depth, and increased goblet and Paneth cells, compared to controls. We also show that HA 35 KDa leads to an increased predominance of Clostridiales Ruminococcaceae, Lactobacillales Lactobacillaceae, and Clostridiales Lachnospiraceae. In seeking the mechanisms involved in the changes, bulk RNA seq was performed on samples from the terminal ileum and identified upregulation in several genes essential for cellular growth, proliferation, and survival. Taken together, this study shows that HA 35 KDa supplemented to mouse pups promotes intestinal epithelial cell proliferation, as well as the development of Paneth cells and goblet cell subsets. HA 35 KDa also impacted the intestinal microbiota; the implications of these responses need to be determined.

Lachnospiraceae

Necrotizing Enterocolitis

Paneth cell

Clostridiales

Goblet cell

10.3390/nu13062030

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Differential Proteomic Responses of Patient-derived Preterm Vs. Term Neonatal Tracheal Airway Epithelial Cells Following Hyperoxia Exposure

A. Ganguly Christopher Carter Hua Zhong Kathryn Burge Lora C. Bailey-Downs

Hyperoxia

10.1164/ajrccm-conference.2024.209.1_meetingabstracts.a6346

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<em>In Vitro </em>Apical-Out Enteroid Model of Necrotizing Enterocolitis

Journal of Visualized Experiments (2022)

Kathryn Burge Adam Wilson Hala Chaaban

Necrotizing Enterocolitis

Adherens junction

Viability assay

10.3791/64003-v

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Early Antibiotic Exposure Alters Intestinal Development and Increases Susceptibility to Necrotizing Enterocolitis: A Mechanistic Study

Microorganisms (2022)

Hala Chaaban Maulin M. Patel Kathryn Burge Jeffrey Eckert Cristina Lupu

Increasing evidence suggests that prolonged antibiotic therapy in preterm infants is associated with increased mortality and morbidities, such as necrotizing enterocolitis (NEC), a devastating gastrointestinal pathology characterized by intestinal inflammation and necrosis. While a clinical correlation exists between antibiotic use and the development of NEC, the potential causality of antibiotics in NEC development has not yet been demonstrated. Here, we tested the effects of systemic standard-of-care antibiotic therapy for ten days on intestinal development in neonatal mice. Systemic antibiotic treatment impaired the intestinal development by reducing intestinal cell proliferation, villi height, crypt depth, and goblet and Paneth cell numbers. Oral bacterial challenge in pups who received antibiotics resulted in NEC-like intestinal injury in more than half the pups, likely due to a reduction in mucous-producing cells affecting microbial-epithelial interactions. These data support a novel mechanism that could explain why preterm infants exposed to prolonged antibiotics after birth have a higher incidence of NEC and other gastrointestinal disorders.

Necrotizing Enterocolitis

Enterocolitis

Paneth cell

10.3390/microorganisms10030519

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Citations (27)

Hyperoxia Exposure Alters Airway Mucociliary Differentiation and Downregulates Mitochondrial Complex I in Patient Sample-derived Neonatal Tracheal Airway Epithelial Cells

Free Radical Biology and Medicine (2024)

Abhrajit Ganguly Cynthia Carter Kathryn Burge Alvaro Moreira Maxwell Mathias

Hyperoxia

10.1016/j.freeradbiomed.2024.10.131

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Biomarkers of necrotizing enterocolitis in the era of machine learning and omics

Seminars in Perinatology (2022)

Tyler Leiva Shiloh R. Lueschow Kathryn Burge Christa I. DeVette Steven J. McElroy

Necrotizing Enterocolitis

Omics

Personalized Medicine

10.1016/j.semperi.2022.151693

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Citations (4)

Clinical Characteristics and Potential Pathogenesis of Cardiac Necrotizing Enterocolitis in Neonates with Congenital Heart Disease: A Narrative Review

Journal of Clinical Medicine (2022)

Kathryn Burge Aarthi Gunasekaran Marjorie Makoni Arshid Mir Harold M. Burkhart

Neonates with congenital heart disease (CHD) are at an increased risk of developing necrotizing enterocolitis (NEC), an acute inflammatory intestinal injury most commonly associated with preterm infants. The rarity of this complex disease, termed cardiac NEC, has resulted in a dearth of information on its pathophysiology. However, a higher incidence in term infants, effects on more distal regions of the intestine, and potentially a differential immune response may distinguish cardiac NEC as a distinct condition from the more common preterm, classical NEC. In this review, risk factors, differentiated from those of classical NEC, are discussed according to their potential contribution to the disease process, and a general pathogenesis is postulated for cardiac NEC. Additionally, biomarkers specific to cardiac NEC, clinical outcomes, and strategies for achieving enteral feeds are discussed. Working towards an understanding of the mechanisms underlying cardiac NEC may aid in future diagnosis of the condition and provide potential therapeutic targets.

Necrotizing Enterocolitis

Pathogenesis

Enterocolitis

10.3390/jcm11143987

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Citations (22)