Biological Phenomena, Cell Phenomena, and Immunity Commons^™

A Narrative Review Of The Ileal Pouch In Pediatric Inflammatory Bowel Disease And Familial Adenomatous Polyposis, Anitta Philip, Allyson Wyatt, Jose R Rodriguez, Brad Pasternak, Lisa Mcmahon, Kalyani Patel, Richard Kellermayer

Faculty, Staff and Students Publications

Ileal pouch-anal anastomosis is a surgical intervention in patients with medically refractory inflammatory bowel disease and familial adenomatous polyposis syndrome. Reported outcomes in children have been limited by both the retrospective nature and sample size of the investigations. In addition, there is a lack of consensus on surveillance guidelines in this patient population. Delay or lack of surveillance may increase the risk of complications (pouchitis, Crohn's disease-like inflammation, dysplasia, etc.). This narrative review aims to summarize the most recent literature (2013-2023) on short-term, long-term, and quality of life (QoL) outcomes in pediatric ileal pouch (J-pouch) patients. A proposed surveillance guidance …

Identifying Novel Fibrotic Mechanisms Underlying Treatment-Resistant Lower Urinary Tract Dysfunction, Quentin Darcy

Graduate Doctoral Dissertations

ABSTRACT

IDENTIFYING NOVEL FIBROTIC MECHANISMS UNDERLYING TREATMENT-RESISTANT LOWER URINARY TRACT DYSFUNCTION

August 2025

Quentin D’Arcy, B.S., University of Massachusetts Amherst

Ph.D., University of Massachusetts Boston

Directed by Dr. Jill Macoska

Lower urinary tract dysfunction (LUTD) is a common, age-related disease that affects millions of men over the age of 50. Current treatment for this and other related prostate diseases concentrate on decreasing benign prostate growth and relaxing smooth muscle contractions to alleviate urinary voiding symptoms. However, up to 45% of patients with LUTD are treatment-resistant and require surgical intervention to resolve prostate issues. By focusing on the contribution of inflammation-derived …

Identification Of Distinct Biological Groups Of Patients With Cryptogenic Norse Via Inflammatory Profiling, Martin Guillemaud, Mario Chavez, Firas Kobeissy, Annamaria Vezzani, Anthony D Jimenez, Maysaa Merhi Basha, Ayush Batra, Sophie Demeret, Onome Eka, Krista Eschbach, Brandon Foreman, Nicolas Gaspard, Elizabeth E Gerard, Teneille Emma Gofton, Hiba A Haider, Stephen T Hantus, Charles L Howe, Amy Jongeling, Mariel Kalkach-Aparicio, Padmaja Kandula, Karnig Kazazian, Minjee Kim, Yi-Chen Lai, Clémence Marois, Andrew Mellor, Wazim Mohamed, Mikaela Morales, Cederic M Pimentel, Alexandra M Ramirez, Claude Steriade, Aaron F Struck, Olga Taraschenko, Nathan Torcida Sedano, Mark S Wainwright, Ji Yeoun Yoo, Kevin K W Wang, Vincent Navarro, Lawrence J Hirsch, Aurélie Hanin

Faculty, Staff and Students Publications

Background and objectives: Emerging evidence suggests that immune dysregulation plays a pivotal role in triggering cryptogenic new-onset refractory status epilepticus (c-NORSE), prompting a consensus on early initiation of immunotherapy. However, despite similar timing of administration, responses to immunotherapies have been varied and unpredictable, suggesting the presence of heterogeneous underlying mechanisms. The aim of this study was to identify distinct inflammatory response subtypes in patients with c-NORSE by analyzing their cytokine profiles. Insights into underlying mechanisms were sought to understand the pathophysiology and guide personalized therapies to improve patient outcomes.

Methods: Sixty-two patients with c-NORSE were included. A comprehensive panel …

Relationships Between Health Behaviors And Markers Of Oxidative Stress And Inflammation On Blood Pressure, Alison M. Godfrey

Honors Scholar Theses

Background. Young adulthood is a period when cardiometabolic risk factors begin to emerge. Developing cardiometabolic risk early can increase the risk and severity of chronic illness across the lifespan. Despite this, young adults are often understudied particularly as it relates to major cardiometabolic risk factors such as blood pressure (BP) and risk of hypertension. Hypertension is a public health crisis and early indicators of hypertension risk should be more thoroughly researched. Therefore, the purpose of the presented thesis is to examine BP in young adults and two potential pathways by which risk may emerge in young adults; inflammation (C-Reactive …

Sialidase Fusion Protein Protects Against Influenza Infection In A Cigarette Smoke-Induced Model Of Copd, Cheng-Yen Chang, Dominique Armstrong, John M Knight, Trevor V Gale, Stephen Hawley, Max Wang, Nancy Chang, David B Corry, Farrah Kheradmand

Faculty, Staff and Students Publications

First- and secondhand smokers are at an increased risk for influenza virus (IFV)-related respiratory failure and death. Despite approved influenza antiviral treatments, there is an unmet need for treatments that can improve outcomes in populations at risk for respiratory failure, including tobacco users with Chronic Obstructive Pulmonary Disease (COPD). Here we show that the sialidase fusion protein, DAS181, reduced viral burden, mitigated inflammation, and attenuated lung function loss, consistent with broad-spectrum anti-influenza responses in a mouse model of COPD and IFV-A infection. Treatment with DAS181 reprogramed the sialic acid-binding immunoglobulin-like lectins (Siglecs) in alveolar macrophages, increased expression of phagocytic marker …

Rare Damaging Ccr2 Variants Are Associated With Lower Lifetime Cardiovascular Risk, Marios K Georgakis, Rainer Malik, Omar El Bounkari, Natalie R Hasbani, Jiang Li, Jennifer E Huffman, Gabrielle Shakt, Reinier W P Tack, Tamara N Kimball, Yaw Asare, Alanna C Morrison, Noah L Tsao, Renae Judy, Braxton D Mitchell, Huichun Xu, May E Montasser, Ron Do, Eimear E Kenny, Ruth J F Loos, James G Terry, John Jeffrey Carr, Joshua C Bis, Bruce M Psaty, W T Longstreth, Kendra A Young, Sharon M Lutz, Michael H Cho, Jai Broome, Alyna T Khan, Fei Fei Wang, Nancy Heard-Costa, Sudha Seshadri, Ramachandran S Vasan, Nicholette D Palmer, Barry I Freedman, Donald W Bowden, Lisa R Yanek, Brian G Kral, Lewis C Becker, Patricia A Peyser, Lawrence F Bielak, Farah Ammous, April P Carson, Michael E Hall, Laura M Raffield, Stephen S Rich, Wendy S Post, Russel P Tracy, Kent D Taylor, Xiuqing Guo, Michael C Mahaney, Joanne E Curran, John Blangero, Shoa L Clarke, Jeffrey W Haessler, Yao Hu, Themistocles L Assimes, Charles Kooperberg, Jürgen Bernhagen, Christopher D Anderson, Scott M Damrauer, Ramin Zand, Jerome I Rotter, Paul S De Vries, Martin Dichgans

Faculty, Staff and Student Publications

BACKGROUND: Previous work has shown a role of CCL2, a key chemokine governing monocyte trafficking, in atherosclerosis. However, it remains unknown whether targeting CCR2, the cognate receptor of CCL2, provides protection against human atherosclerotic cardiovascular disease.

METHODS: Computationally predicted damaging or loss-of-function (REVEL > 0.5) variants within CCR2 were detected in whole-exome-sequencing data from 454,775 UK Biobank participants and tested for association with cardiovascular endpoints in gene-burden tests. Given the key role of CCR2 in monocyte mobilization, variants associated with lower monocyte count were prioritized for experimental validation. The response to CCL2 of human cells transfected with these variants was tested …

The Long Road Of Drug Development For Endometriosis – Pains, Gains, And Hopes, Zian Liao, Diana Monsivais, Martin M Matzuk

Faculty, Staff and Students Publications

Endometriosis, defined by the growth of endometrial tissues outside of the uterine cavity, is a global health burden for ∼200 million women. Patients with endometriosis usually present with chronic pain and are often diagnosed with infertility. The pathogenesis of endometriosis is still an open question; however, tissue stemness and immunological and genetic factors have been extensively discussed in the establishment of endometriotic lesions. Current treatments for endometriosis can be categorized into pharmacological management of hormone levels and surgical removal of the lesions. Both approaches have limited efficacy, with recurrences often encountered; thus, there is no complete cure for the disease …

Aging- And Alcohol-Associated Spatial Transcriptomic Signature In Mouse Acute Pancreatitis Reveals Heterogeneity Of Inflammation And Potential Pathogenic Factors, Rachel R Tindall, Yuntao Yang, Isabella Hernandez, Amy Qin, Jiajing Li, Yinjie Zhang, Thomas H Gomez, Mamoun Younes, Qiang Shen, Jennifer M Bailey-Lundberg, Zhongming Zhao, Daniel Kraushaar, Patricia Castro, Yanna Cao, W Jim Zheng, Tien C Ko

Faculty, Staff and Student Publications

The rapidly aging population is consuming more alcohol, leading to increased alcohol-associated acute pancreatitis (AAP) with high mortality. However, the mechanisms remain undefined, and currently there are no effective therapies available. This study aims to elucidate aging- and alcohol-associated spatial transcriptomic signature by establishing an aging AAP mouse model and applying Visium spatial transcriptomics for understanding of the mechanisms in the context of the pancreatic tissue. Upon alcohol diet feeding and caerulein treatment, aging mice (18 months) developed significantly more severe AAP with 5.0-fold increase of injury score and 2.4-fold increase of amylase compared to young mice (3 months). Via …

Individuals With Jak1 Variants Are Affected By Syndromic Features Encompassing Autoimmunity, Atopy, Colitis, And Dermatitis, Michael E Horesh, Marta Martin-Fernandez, Conor Gruber, Sofija Buta, Tom Le Voyer, Eve Puzenat, Harry Lesmana, Yiming Wu, Ashley Richardson, David Stein, Stephanie Hodeib, Mariam Youssef, Jacob A Kurowski, Elizabeth Feuille, Luis A Pedroza, Ramsay L Fuleihan, Alexandria Haseley, Alain Hovnanian, Pierre Quartier, Jérémie Rosain, Georgina Davis, Daniel Mullan, O'Jay Stewart, Roosheel Patel, Angelica E Lee, Rebecca Rubinstein, Leyla Ewald, Nikhil Maheshwari, Virginia Rahming, Ivan K Chinn, James R Lupski, Jordan S Orange, Vanessa Sancho-Shimizu, Jean-Laurent Casanova, Noura S Abul-Husn, Yuval Itan, Joshua D Milner, Jacinta Bustamante, Dusan Bogunovic

Faculty, Staff and Students Publications

Inborn errors of immunity lead to autoimmunity, inflammation, allergy, infection, and/or malignancy. Disease-causing JAK1 gain-of-function (GoF) mutations are considered exceedingly rare and have been identified in only four families. Here, we use forward and reverse genetics to identify 59 individuals harboring one of four heterozygous JAK1 variants. In vitro and ex vivo analysis of these variants revealed hyperactive baseline and cytokine-induced STAT phosphorylation and interferon-stimulated gene (ISG) levels compared with wild-type JAK1. A systematic review of electronic health records from the BioME Biobank revealed increased likelihood of clinical presentation with autoimmunity, atopy, colitis, and/or dermatitis in JAK1 variant-positive individuals. Finally, …

Charting The Cellular Biogeography In Colitis Reveals Fibroblast Trajectories And Coordinated Spatial Remodeling, Paolo Cadinu, Kisha N Sivanathan, Aditya Misra, Rosalind J Xu, Davide Mangani, Evan Yang, Joseph M Rone, Katherine Tooley, Yoon-Chul Kye, Lloyd Bod, Ludwig Geistlinger, Tyrone Lee, Randall T Mertens, Noriaki Ono, Gang Wang, Liliana Sanmarco, Francisco J Quintana, Ana C Anderson, Vijay K Kuchroo, Jeffrey R Moffitt, Roni Nowarski

Faculty, Staff and Student Publications

Gut inflammation involves contributions from immune and non-immune cells, whose interactions are shaped by the spatial organization of the healthy gut and its remodeling during inflammation. The crosstalk between fibroblasts and immune cells is an important axis in this process, but our understanding has been challenged by incomplete cell-type definition and biogeography. To address this challenge, we used multiplexed error-robust fluorescence in situ hybridization (MERFISH) to profile the expression of 940 genes in 1.35 million cells imaged across the onset and recovery from a mouse colitis model. We identified diverse cell populations, charted their spatial organization, and revealed their polarization …

The Saga Of E Faecium, Rishika Prasad, Robert R Jenq

Faculty, Staff and Student Publications

An enzyme that remodels the cell wall of Enterococcus faecium helps these gut bacteria to divide and generate peptide fragments that enhance the immune response against cancer.

The Fatigue-Inducing Effects Of Cancer And Its Therapy Are Characterized By Decreased Physical Activity In The Absence Of Any Motivational Deficit, Thien T Phan, Kiersten S Scott, Brandon Chelette, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Although cancer and its therapy are well known to be associated with fatigue, the exact nature of cancer-related fatigue remains ill-defined. We previously reported that fatigue-like behavior induced independently by tumor growth and by the chemotherapeutic agent cisplatin is characterized by reduced voluntary wheel running and an intact motivation to expand effort for food rewards. The present set of experiments was initiated to characterize the functional consequences of fatigue induced by chemoradiotherapy in tumor-bearing mice and relate them to changes in the expression of genes coding for inflammation, mitochondria dynamics and metabolism. Two syngeneic murine models of cancer were selected …

Txnrd1 Drives The Innate Immune Response In Senescent Cells With Implications For Age-Associated Inflammation, Xue Hao, Bo Zhao, Martina Towers, Liping Liao, Edgar Luzete Monteiro, Xin Xu, Christina Freeman, Hongzhuang Peng, Hsin-Yao Tang, Aaron Havas, Andrew V Kossenkov, Shelley L Berger, Peter D Adams, David W Speicher, David Schultz, Ronen Marmorstein, Kenneth S Zaret, Rugang Zhang

Faculty, Staff and Student Publications

Sterile inflammation, also known as 'inflammaging', is a hallmark of tissue aging. Cellular senescence contributes to tissue aging, in part, through the secretion of proinflammatory factors collectively known as the senescence-associated secretory phenotype (SASP). The genetic variability of thioredoxin reductase 1 (TXNRD1) is associated with aging and age-associated phenotypes such as late-life survival, activity of daily living and physical performance in old age. TXNRD1's role in regulating tissue aging has been attributed to its enzymatic role in cellular redox regulation. Here, we show that TXNRD1 drives the SASP and inflammaging through the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) …

Proteome Analysis For Inflammation Related To Acute And Convalescent Infection, Tara K Sigdel, Swastika Sur, Patrick Boada, Suzanne M Mcdermott, Cecilia S Lindestam Arlehamn, Kristy O Murray, Linda K Bockenstedt, Maggie Kerwin, Elaine F Reed, Eva Harris, Ken Stuart, Bjoern Peters, Ana Sesma, Ruth R Montgomery, Minnie M Sarwal

Faculty, Staff and Students Publications

Infectious diseases are a significant burden in global healthcare. Pathogens engage with different host defense mechanisms. However, it is currently unknown if there are disease-specific immune signatures and/or if different pathogens elicit common immune-associated molecular entities to common therapeutic interventions. We studied patients enrolled through the Human Immunology Project Consortium (HIPC), which focuses on immune responses to various infections. Blood samples were collected and analyzed from patients during infection and follow-up time points at the convalescent stage. The study included samples from patients with Lyme disease (LD), tuberculosis (TB), malaria (MLA), dengue virus (DENV), and West Nile virus (WNV), as …

Neuronal Ablation Of Ghsr Mitigates Diet-Induced Depression And Memory Impairment Via Ampk-Autophagy Signaling-Mediated Inflammation, Hongying Wang, Zheng Shen, Chia-Shan Wu, Pengfei Ji, Ji Yeon Noh, Cédric G Geoffroy, Sunja Kim, David Threadgill, Jianrong Li, Yu Zhou, Xiaoqiu Xiao, Hui Zheng, Yuxiang Sun

Faculty, Staff and Students Publications

Obesity is associated with chronic inflammation in the central nervous system (CNS), and neuroinflammation has been shown to have detrimental effects on mood and cognition. The growth hormone secretagogue receptor (GHSR), the biologically relevant receptor of the orexigenic hormone ghrelin, is primarily expressed in the brain. Our previous study showed that neuronal GHSR deletion prevents high-fat diet-induced obesity (DIO). Here, we investigated the effect of neuronal GHSR deletion on emotional and cognitive functions in DIO. The neuron-specific GHSR-deficient mice exhibited reduced depression and improved spatial memory compared to littermate controls under DIO. We further examined the cortex and hippocampus, the …

High-Fat Diets Promote Peritoneal Inflammation And Augment Endometriosis-Associated Abdominal Hyperalgesia, Tristin Herup-Wheeler, Mingxin Shi, Madeleine E Harvey, Chandni Talwar, Ramakrishna Kommagani, James A Maclean, Kanako Hayashi

Faculty, Staff and Students Publications

Immune dysfunction is one of the central components in the development and progression of endometriosis by establishing a chronic inflammatory environment. Western-style high-fat diets (HFD) have been linked to greater systemic inflammation to cause metabolic and chronic inflammatory diseases, and are also considered an environmental risk factor for gynecologic diseases. Here, we aimed to examine how HFD cause an inflammatory environment in endometriosis and discern their contribution to endometriotic-associated hyperalgesia. Our results showed that HFD-induced obesity enhanced abdominal hyperalgesia that was induced by endometriotic lesions. Peritoneal inflammatory macrophages and cytokine levels increased by lesion induction were elevated by chronic exposure …

Neutrophil-Derived Activin-A Moderates Their Pro-Netotic Activity And Attenuates Collateral Tissue Damage Caused By Influenza A Virus Infection, Georgios Divolis, Evgenia Synolaki, Athanasia Doulou, Ariana Gavriil, Christina C Giannouli, Anastasia Apostolidou, Martyn L Foster, Martin M Matzuk, Panagiotis Skendros, Ioanna-Evdokia Galani, Paschalis Sideras

Faculty, Staff and Students Publications

BACKGROUND: Pre-neutrophils, while developing in the bone marrow, transcribe the Inhba gene and synthesize Activin-A protein, which they store and release at the earliest stage of their activation in the periphery. However, the role of neutrophil-derived Activin-A is not completely understood.

METHODS:To address this issue, we developed a neutrophil-specific Activin-A-deficient animal model (S100a8-Cre/Inhba fl/fl mice) and analyzed the immune response to Influenza A virus (IAV) infection. More specifically, evaluation of body weight and lung mechanics, molecular and cellular analyses of bronchoalveolar lavage fluids, flow cytometry and cell sorting of lung cells, as well as histopathological analysis of lung tissues, …

Therapeutic Effect Of Echinococcus Granulosus Cyst Fluid On Bacterial Sepsis In Mice, Shuying Wang, Donghui Jiang, Feifei Huang, Yayun Qian, Meitao Qi, Huihui Li, Xiaoli Wang, Zhi Wang, Kaigui Wang, Yin Wang, Pengfei Du, Bin Zhan, Rui Zhou, Liang Chu, Xiaodi Yang

Faculty, Staff and Students Publications

BACKGROUND: The primary pathophysiological process of sepsis is to stimulate a massive release of inflammatory mediators to trigger systemic inflammatory response syndrome (SIRS), the major cause of multi-organ dysfunction and death. Like other helminths, Echinococcus granulosus induces host immunomodulation. We sought to determine whether E. granulosus cyst fluid (EgCF) displays a therapeutic effect on sepsis-induced inflammation and tissue damage in a mouse model.

METHODS: The anti-inflammatory effects of EgCF were determined by in vitro culture with bone marrow-derived macrophages (BMDMs) and in vivo treatment of BALB/C mice with cecal ligation and puncture (CLP)-induced sepsis. The macrophage phenotypes were determined by …

Microbial Products Linked To Steatohepatitis Are Reduced By Deletion Of Nuclear Hormone Receptor Shp In Mice, Ryan Mifflin, Jung Eun Park, Mikang Lee, Prasant Kumar Jena, Yu-Jui Yvonne Wan, Hazel A Barton, Mirjavid Aghayev, Takhar Kasumov, Li Lin, Xinwen Wang, Robert Novak, Feng Li, He Huang, Leah P Shriver, Yoon-Kwang Lee

Faculty, Staff and Students Publications

Deletion of the nuclear hormone receptor small heterodimer partner (Shp) ameliorates the development of obesity and nonalcoholic steatohepatitis (NASH) in mice. Liver-specific SHP plays a significant role in this amelioration. The gut microbiota has been associated with these metabolic disorders, and the interplay between bile acids (BAs) and gut microbiota contributes to various metabolic disorders. Since hepatic SHP is recognized as a critical regulator in BA synthesis, we assessed the involvement of gut microbiota in the antiobesity and anti-NASH phenotype of Shp−/− mice. Shp deletion significantly altered the levels of a few conjugated BAs. Sequencing the 16S …

Excretory/Secretory Products From Trichinella Spiralis Adult Worms Ameliorate Myocardial Infarction By Inducing M2 Macrophage Polarization In A Mouse Model, Lingqin Wu, Wenhui Yin, Jutai Wen, Shuying Wang, Huihui Li, Xiaoli Wang, Weixiao Zhang, Shuyao Duan, Qiuyu Zhu, Erhe Gao, Shili Wu, Bin Zhan, Rui Zhou, Xiaodi Yang

Faculty, Staff and Students Publications

BACKGROUND: Ischemia-induced inflammatory response is the main pathological mechanism of myocardial infarction (MI)-caused heart tissue injury. It has been known that helminths and worm-derived proteins are capable of modulating host immune response to suppress excessive inflammation as a survival strategy. Excretory/secretory products from Trichinella spiralis adult worms (Ts-AES) have been shown to ameliorate inflammation-related diseases. In this study, Ts-AES were used to treat mice with MI to determine its therapeutic effect on reducing MI-induced heart inflammation and the immunological mechanism involved in the treatment.

METHODS: The MI model was established by the ligation of the left anterior descending coronary artery, …

Fibroblast-Derived Pi16 Sustains Inflammatory Pain Via Regulation Of Cd206+ Myeloid Cells, Rachelle Garrity, Neha Arora, Md Areeful Haque, Drew Weis, Ronnie T Trinh, Sanjay V Neerukonda, Susmita Kumari, Ibdanelo Cortez, Eroboghene E Ubogu, Rajasekaran Mahalingam, Diana Tavares-Ferreira, Theodore J Price, Annemieke Kavelaars, Cobi J Heijnen, Andrew J Shepherd

Faculty, Staff and Student Publications

Originally identified in fibroblasts, Protease Inhibitor (PI)16 was recently shown to be crucial for the development of neuropathic pain via effects on blood-nerve barrier permeability and leukocyte infiltration, though its impact on inflammatory pain has not been established. Using the complete Freund’s Adjuvant inflammatory pain model, we show that Pi16-/- mice are protected against sustained inflammatory pain. Accordingly, intrathecal delivery of a PI16 neutralizing antibody in wild-type mice prevented sustained CFA pain. In contrast to neuropathic pain models, we did not observe any changes in blood-nerve barrier permeability due to PI16 deletion. Instead, Pi16-/- mice display reduced macrophage density …

Cancer Cell-Specific Cgas/Sting Signaling Pathway In The Era Of Advancing Cancer Cell Biology, Vijay Kumar, Caitlin Bauer, John H. Stewart

School of Graduate Studies Faculty Publications

Pattern-recognition receptors (PRRs) are critical to recognizing endogenous and exogenous threats to mount a protective proinflammatory innate immune response. PRRs may be located on the outer cell membrane, cytosol, and nucleus. The cGAS/STING signaling pathway is a cytosolic PRR system. Notably, cGAS is also present in the nucleus. The cGAS-mediated recognition of cytosolic dsDNA and its cleavage into cGAMP activates STING. Furthermore, STING activation through its downstream signaling triggers different interferon-stimulating genes (ISGs), initiating the release of type 1 interferons (IFNs) and NF-κB-mediated release of proinflammatory cytokines and molecules. Activating cGAS/STING generates type 1 IFN, which may prevent cellular transformation …

Immunomodulatory Effects Of Resolvin D2 In A Model Of Infection, Prem Yugandhar Kadiyam Sundarasivarao

Graduate School of Biomedical Sciences Theses and Dissertations

Dysregulated hyperinflammatory host immune response to underlying bacterial infections is a characteristic of sepsis. In sepsis, bacteria often trigger abnormal hyperinflammatory responses which can cause multiple organ failure and if sustained can lead to an immunosuppressive phase where the host is susceptible to secondary infections caused by opportunistic bacteria like Pseudomonas aeruginosa (P. aeruginosa). In our studies, we used a 2-hit model of cecal ligation and puncture (CLP) followed by P. aeruginosa secondary lung infection to investigate cellular and molecular mechanisms in the beneficial action of resolvin D2 (RvD2). Resolvins of the D-series are a group of fatty acids known …

Endogenous Interleukin-10 Contributes To Wound Healing And Regulates Tissue Repair, Walker D Short, Meredith Rae, Thomas Lu, Benjamin Padon, Tanuj J Prajapati, Fayiz Faruk, Oluyinka O Olutoye, Ling Yu, Paul Bollyky, Sundeep G Keswani, Swathi Balaji

Faculty, Staff and Students Publications

INTRODUCTION: Interleukin-10 (IL-10) is essential in fetal regenerative wound healing and likewise promotes a regenerative phenotype in adult dermal wounds. However, the role of endogenous IL-10 in postnatal dermal wound healing is not well-established. We sought to determine the function of endogenous IL-10 in murine full thickness excisional wounds that are splinted to prevent contracture and mimic human patterns of wound closure.

METHODS: Full-thickness excisional wounds were made in wildtype (WT) and IL-10

RESULTS: We observed no difference in wound healing rate between WT and IL-10

CONCLUSIONS: These data suggest that endogenous IL-10 expression does not alter closure of full …

Hyaluronan In The Pathogenesis Of Acute And Post-Acute Covid-19 Infection, Henry W Barnes, Sally Demirdjian, Naomi L Haddock, Gernot Kaber, Hunter A Martinez, Nadine Nagy, Harry Karmouty-Quintana, Paul L Bollyky

Faculty, Staff and Student Publications

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) recently emerged as the cause of a global pandemic. Infection with SARS-CoV-2 can result in COVID-19 with both acute and chronic disease manifestations that continue to impact many patients long after the resolution of viral replication. There is therefore great interest in understanding the host factors that contribute to COVID-19 pathogenesis. In this review, we address the role of hyaluronan (HA), an extracellular matrix polymer with roles in inflammation and cellular metabolism, in COVID-19 and critically evaluate the hypothesis that HA promotes COVID-19 pathogenesis. We first provide a brief overview of COVID-19 infection. …

Supplementing Glycine And N-Acetylcysteine (Glynac) In Older Adults Improves Glutathione Deficiency, Oxidative Stress, Mitochondrial Dysfunction, Inflammation, Physical Function, And Aging Hallmarks: A Randomized Clinical Trial, Premranjan Kumar, Chun Liu, James Suliburk, Jean W Hsu, Raja Muthupillai, Farook Jahoor, Charles G Minard, George E Taffet, Rajagopal V Sekhar

Faculty, Staff and Students Publications

BACKGROUND: Elevated oxidative stress (OxS), mitochondrial dysfunction, and hallmarks of aging are identified as key contributors to aging, but improving/reversing these defects in older adults (OA) is challenging. In prior studies, we identified that deficiency of the intracellular antioxidant glutathione (GSH) could play a role and reported that supplementing GlyNAC (combination of glycine and N-acetylcysteine [NAC]) in aged mice improved GSH deficiency, OxS, mitochondrial fatty-acid oxidation (MFO), and insulin resistance (IR). To test whether GlyNAC supplementation in OA could improve GSH deficiency, OxS, mitochondrial dysfunction, IR, physical function, and aging hallmarks, we conducted a placebo-controlled randomized clinical trial.

METHODS: Twenty-four …

Evolutionary Aspects Of Infections: Inflammation And Sickness Behaviors, Robert Dantzer

Faculty, Staff and Student Publications

Sickness behavior was conceptualized initially as the behavioral counterpart of the fever response to infectious pathogens. It helps to raise body temperature to its higher setpoint and to maintain it at this new level and it has the additional benefit of enabling a weakened organism to protect itself from other dangers. The discovery of the behavioral effects of proinflammatory cytokines produced by activated immune cells provided a cellular and molecular basis to this phenomenon. The administration of cytokines or cytokine inducers like lipopolysaccharide to healthy rodents allowed to reveal the similarities and differences between inflammation-induced sickness behavior and the fever …

Beneficial Impacts Of Nod-Like Receptor X1(Nlrx1) Agonism In Lipopolysaccharide-Induced Inflammation, Mena Mansy

Graduate Theses, Dissertations, and Problem Reports (ETD)

Introduction: The regulation of inflammation at the cellular and molecular level is a crucial aspect of homeostasis that is often overlooked, and most treatment options are limited to antibiotics and symptom management drugs. The development of novel molecular-targeted therapy options downstream of pathogen recognition receptors will fulfill the unmet need for therapy to effectively regulate excessive inflammation. NLRX1 is a unique NOD-like receptor that is anti-inflammatory in nature; it has been shown to negatively regulate the NF-kB pathway and has been involved in the pathology of a plethora of inflammatory disorders. This makes NLRX1 an emerging therapeutic molecular target for …

Vaccine-Linked Chemotherapy Improves Cardiac Structure And Function In A Mouse Model Of Chronic Chagas Disease, Kathryn M Jones, Elise N Mangin, Corey L Reynolds, Liliana E Villanueva, Julio Vladimir Cruz, Leroy Versteeg, Brian Keegan, April Kendricks, Jeroen Pollet, Fabian Gusovsky, Maria Elena Bottazzi, Peter J Hotez

Faculty, Staff and Students Publications

INTRODUCTION: Chagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. …

Metabolome And Microbiome Multi-Omics Integration From A Murine Lung Inflammation Model Of Bronchopulmonary Dysplasia, Ahmed El Saie, Chenlian Fu, Sandra L Grimm, Matthew J Robertson, Kristi Hoffman, Vasanta Putluri, Chandra Shekar R Ambati, Nagireddy Putluri, Binoy Shivanna, Cristian Coarfa, Mohan Pammi

Faculty, Staff and Students Publications

BACKGROUND: Respiratory tract microbial dysbiosis can exacerbate inflammation and conversely inflammation may cause dysbiosis. Dysbiotic microbiome metabolites may lead to bronchopulmonary dysplasia (BPD). Hyperoxia and lipopolysaccharide (LPS) interaction alters lung microbiome and metabolome, mediating BPD lung injury sequence.

METHODS: C57BL6/J mice were exposed to 21% (normoxia) or 70% (hyperoxia) oxygen during postnatal days (PND) 1-14. Pups were injected with LPS (6 mg/kg) or equal PBS volume, intraperitoneally on PND 3, 5, and 7. At PND14, the lungs were collected for microbiome and metabolomic analyses (n = 5/group).

RESULTS: Microbiome alpha and beta diversity were similar between groups. Metabolic changes included …