The hypoxia-adenosine link during inflammation

Hypoxic tissue conditions occur during a number of inflammatory diseases and are associated with the breakdown of barriers and induction of proinflammatory responses. At the same time, hypoxia is also known to induce several adaptive and tissue-protective pathways that dampen inflammation and protect tissue integrity. Hypoxia-inducible factors (HIFs) that are stabilized during inflammatory or hypoxic conditions are at the center of mediating these responses. In the past decade, several genes regulating extracellular adenosine metabolism and signaling have been identified as being direct targets of HIFs. Here, we discuss the relationship between inflammation, hypoxia, and adenosine and that HIF-driven adenosine metabolism and signaling is essential in providing tissue protection during inflammatory conditions, including myocardial injury, inflammatory bowel disease, and acute lung injury. We also discuss how the hypoxia-adenosine link can be targeted therapeutically in patients as a future treatment approach for inflammatory diseases.

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Hiding in Plain Sight: Interleukin-11 Emerges as a Master Regulator of Fibrosis, Tissue Integrity, and Stromal Inflammation

Annual Review of Medicine ◽

10.1146/annurev-med-041818-011649 ◽

2020 ◽

Vol 71 (1) ◽

pp. 263-276 ◽

Cited By ~ 11

Author(s):

Stuart A. Cook ◽

Sebastian Schafer

Keyword(s):

Tissue Regeneration ◽

Inflammatory Diseases ◽

Parenchymal Cell ◽

Drug Induced ◽

Drug Induced Liver Injury ◽

Cell Dysfunction ◽

Tissue Integrity ◽

Polarized Cells ◽

Inflammatory Bowel ◽

Interleukin 11

Interleukin (IL)-11 is upregulated in a wide variety of fibro-inflammatory diseases such as systemic sclerosis, rheumatoid arthritis, pulmonary fibrosis, inflammatory bowel disease, kidney disease, drug-induced liver injury, and nonalcoholic steatohepatitis. IL-11 is a member of the IL-6 cytokine family and has several distinct properties that define its unique and nonredundant roles in disease. The IL-11 receptor is highly expressed on stromal, epithelial and polarized cells, where noncanonical IL-11 signaling drives the three pathologies common to all fibro-inflammatory diseases—myofibroblast activation, parenchymal cell dysfunction, and inflammation—while also inhibiting tissue regeneration. This cytokine has been little studied, and publications on IL-11 peaked in the early 1990s, when it was largely misunderstood. Here we describe recent advances in our understanding of IL-11 biology, outline how misconceptions as to its function came about, and highlight the large potential of therapies targeting IL-11 signaling for treating human disease.

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Practical Guidelines for Managing Patients With Psoriasis on Biologics: An Update

Journal of Cutaneous Medicine and Surgery ◽

10.1177/1203475418811347 ◽

2019 ◽

Vol 23 (1_suppl) ◽

pp. 3S-12S ◽

Cited By ~ 6

Author(s):

Susan M. Poelman ◽

Christopher P. Keeling ◽

Andrei I. Metelitsa

Keyword(s):

Health Care Providers ◽

Primary Care Physicians ◽

Inflammatory Diseases ◽

Biologic Agents ◽

Targeted Therapeutics ◽

Care Providers ◽

The Past ◽

Practical Guidelines ◽

Inflammatory Bowel ◽

Systemic Therapies

The paradigm for treating inflammatory diseases has shifted dramatically in the past 10 to 20 years with the discovery of targeted therapeutics or “biologic” agents. Patients with rheumatoid arthritis, inflammatory bowel disease, psoriatic arthritis, and psoriasis, among others, are reaping the benefits of decades of bench to bedside research, allowing them to live more productive lives with less side effects than traditional systemic therapies. Despite these advances, many physicians unfamiliar with biologics are left to care for the basic needs of these patients and may be unaware of the multisystem comorbidities associated with psoriasis and the screening, monitoring, and other special considerations required of biologics patients. This can be overwhelming to primary care physicians and inadvertently expose patients to undue risks. The aim of this review is to provide a practical approach for all health care providers caring for patients with psoriasis being treated with biologics to facilitate communication with their treating dermatologist and ultimately provide patients with more comprehensive care.

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Postbiotics: what else?

Beneficial Microbes ◽

10.3920/bm2012.0046 ◽

2013 ◽

Vol 4 (1) ◽

pp. 101-107 ◽

Cited By ~ 93

Author(s):

K. Tsilingiri ◽

M. Rescigno

Keyword(s):

Food Industry ◽

Culture Supernatant ◽

Clinical Applications ◽

The Past ◽

Balanced Diet ◽

Inflammatory Conditions ◽

Gut Homeostasis ◽

Probiotic Strains ◽

Inflammatory Bowel ◽

Small And Large Intestine

The use of probiotics and synbiotics in the food industry or as food supplements for a balanced diet and improved gut homeostasis has been blooming for the past decade. As feedback from healthy consumers is rather enthusiastic, a lot of effort is currently directed in elucidating the mechanisms of interaction between beneficial microbes and barrier and immune function of the host. The use of probiotics or synbiotics for treating certain pathologies has also been examined, however, the outcome has not always been favourable. In most cases, the effect of the administered probiotic is evident when the bacteria are still alive at the time they reach the small and large intestine, suggesting that it is dependent on the metabolic activity of the bacteria. Indeed, in some occasions it has been shown that the culture supernatant of these bacteria mediates the immunomodulatory effect conferred to the host. Recent work on relevant probiotic strains has also led to the isolation and characterisation of certain probiotic-produced, soluble factors, here called postbiotics, which were sufficient to elicit the desired response. Here, we summarise these recent findings and propose the use of purified and well characterised postbiotic components as a safer alternative for clinical applications, especially in chronic inflammatory conditions like inflammatory bowel disease, where probiotics have not yet given encouraging results as far as induction of remission is concerned.

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Frailty in inflammatory bowel diseases: an emerging concept

Therapeutic Advances in Gastroenterology ◽

10.1177/17562848211025474 ◽

2021 ◽

Vol 14 ◽

pp. 175628482110254

Author(s):

Bharati Kochar ◽

Ariela R. Orkaby ◽

Ashwin N. Ananthakrishnan ◽

Christine S. Ritchie

Keyword(s):

Older Adults ◽

Inflammatory Bowel Diseases ◽

Conceptual Models ◽

Younger Adults ◽

Inflammatory Conditions ◽

Immune Mediated ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

The Relationship ◽

Improve Health

Inflammatory bowel diseases (IBD), consisting of Crohn’s disease and ulcerative colitis, are chronic remitting, relapsing inflammatory conditions of the gastrointestinal tract. While traditionally a disease of younger ages, the number of older adults with IBD is rising rapidly. Patients with IBD often experience geriatric syndromes at earlier ages. Older adults with IBD have poorer disease and treatment-related outcomes compared with younger adults with IBD. Applying the principles of geriatrics to understanding a chronic disease in older adults may improve health span. Better tools are needed to stratify IBD patients who are at high risk for adverse events. Frailty is a geriatric construct that may approximate biologic age. Frailty is a complex, multi-dimensional syndrome that leads to increased vulnerability to stress and decline of reserve across multiple physiologic systems. In this review, we present the leading conceptual models of frailty and discuss the applications of frailty in immune-mediated diseases. We also review chronic conditions where frailty has been applied successfully as a tool for risk stratification. Finally, we discuss in the detail the growing body of literature highlighting the relationship between frailty and IBD, the epidemiology of frailty in IBD, and ramifications of frailty in IBD.

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Synergy in Cystic Fibrosis Therapies: Targeting SLC26A9

International Journal of Molecular Sciences ◽

10.3390/ijms222313064 ◽

2021 ◽

Vol 22 (23) ◽

pp. 13064

Author(s):

Madalena C. Pinto ◽

Margarida C. Quaresma ◽

Iris A. L. Silva ◽

Violeta Railean ◽

Sofia S. Ramalho ◽

...

Keyword(s):

Cystic Fibrosis ◽

Respiratory Disorders ◽

Cl Secretion ◽

The Past ◽

Inflammatory Conditions ◽

Disease Modifier ◽

And Function ◽

The Relationship ◽

Bronchial Cells ◽

Constitutively Active

SLC26A9, a constitutively active Cl− transporter, has gained interest over the past years as a relevant disease modifier in several respiratory disorders including Cystic Fibrosis (CF), asthma, and non-CF bronchiectasis. SLC26A9 contributes to epithelial Cl− secretion, thus preventing mucus obstruction under inflammatory conditions. Additionally, SLC26A9 was identified as a CF gene modifier, and its polymorphisms were shown to correlate with the response to drugs modulating CFTR, the defective protein in CF. Here, we aimed to investigate the relationship between SLC26A9 and CFTR, and its role in CF pathogenesis. Our data show that SLC26A9 expression contributes to enhanced CFTR expression and function. While knocking-down SLC26A9 in human bronchial cells leads to lower wt- and F508del-CFTR expression, function, and response to CFTR correctors, the opposite occurs upon its overexpression, highlighting SLC26A9 relevance for CF. Accordingly, F508del-CFTR rescue by the most efficient correctors available is further enhanced by increasing SLC26A9 expression. Interestingly, SLC26A9 overexpression does not increase the PM expression of non-F508del CFTR traffic mutants, namely those unresponsive to corrector drugs. Altogether, our data indicate that SLC26A9 stabilizes CFTR at the ER level and that the efficacy of CFTR modulator drugs may be further enhanced by increasing its expression.

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Radiotherapy treatment of human inflammatory diseases and conditions: Optimal dose

Human & Experimental Toxicology ◽

10.1177/0960327119846925 ◽

2019 ◽

Vol 38 (8) ◽

pp. 888-898 ◽

Cited By ~ 29

Author(s):

EJ Calabrese ◽

G Dhawan ◽

R Kapoor ◽

WJ Kozumbo

Keyword(s):

Inflammatory Diseases ◽

Optimal Dose ◽

Past Century ◽

Safe Alternative ◽

The Past ◽

Inflammatory Conditions ◽

Optimal Dosing ◽

Efficacious Treatment ◽

Radiotherapy Treatment

During the early part of the past century, hundreds of clinical studies involving more than 37,000 patients were conducted that showed radiotherapy (RT) to be a successful and safe alternative to drug therapy for the treatment of many diverse inflammatory conditions and diseases (e.g. tendonitis, bursitis, arthritis, and serious inflammatory lung conditions). Data from these studies were collected and analyzed with the intent of estimating an optimal dosing range for RT that would induce an efficacious treatment response. RT was reported to be frequently effective after only a single treatment, with a rapid (within 24 h) and often long-lasting (from months to years) relief from symptoms. Over a two-decade span from the 1920s to the 1940s, the therapeutic responses to a single RT treatment consistently improved as the dosing for multiple ailments decreased over time to between 30 roentgen (r) and 100 r. These findings are significant and in agreement with a number of contemporary reports from Germany where RT has been commonly and successfully employed in treating ailments with an inflammatory origin. A proposed mechanism by which RT mitigates inflammation and facilitates healing is via the polarization of macrophages to an anti-inflammatory or M2 phenotype.

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IBD considerations in spondyloarthritis

Therapeutic Advances in Musculoskeletal Disease ◽

10.1177/1759720x20939410 ◽

2020 ◽

Vol 12 ◽

pp. 1759720X2093941

Author(s):

Caroline Di Jiang ◽

Tim Raine

Keyword(s):

Inflammatory Diseases ◽

Drug Dosing ◽

Inflammatory Conditions ◽

Gastrointestinal Pathology ◽

Immune Mediated ◽

Form Part ◽

Bowel Diseases ◽

Inflammatory Bowel ◽

Gastrointestinal Inflammation ◽

The Difference

Spondyloarthritis (SpA) may be regarded a family of auto-inflammatory conditions with inflammation focused on the joints. These form part of a wider family of immune-mediated inflammatory diseases, which include inflammatory bowel diseases (IBD). These conditions share common elements of pathophysiology and it is perhaps unsurprising, therefore, that individuals with SpA frequently manifest gastrointestinal inflammation, to which the physician managing the patient with SpA must be alert. In this article, we review the shared epidemiology and pathophysiology of these conditions, before discussing approaches to diagnosis and management of inflammatory gastrointestinal pathology in patients seen in rheumatology clinics. In particular, we discuss the difference between non-specific gastrointestinal inflammation commonly described in this patient group and the more specific diagnosis of Crohn’s disease or ulcerative colitis. We describe the appropriate diagnostic workup for patients suspected of having IBD. In addition, we discuss how a diagnosis of IBD can inform treatment selection, highlighting important differences in treatment choice, drug dosing, monitoring and drug safety for this particular comorbid patient population.

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Eosinophilic appendicitis due to Strongyloides stercoralis: a challenging differential diagnosis for clinicians

BMJ Case Reports ◽

10.1136/bcr-2020-239685 ◽

2021 ◽

Vol 14 (6) ◽

pp. e239685

Author(s):

Javier Páramo-Zunzunegui ◽

Laura Rubio-López ◽

Silvia Benito-Barbero ◽

Ángeles Muñoz-Fernández

Keyword(s):

Inflammatory Diseases ◽

Parasitic Infection ◽

Strongyloides Stercoralis ◽

Clinical Findings ◽

The Past ◽

Ultrasound Study ◽

Therapeutic Choice ◽

Inflammatory Bowel ◽

Clinical Awareness ◽

Initial Choice

A 45-year-old man presents with 48-hour status of high temperature, cough and dyspnoea. In the context of pandemic, the patient is initially diagnosed with COVID-19 syndrome. Later, the laboratory and ultrasound study supported acute appendicitis diagnosis. Appendicectomy was performed. The histopathology study confirmed eosinophilic appendicitis and that a parasitic infection was suspected. The stool sample was positive for Strongyloides stercoralis. The diagnosis of a S.stercoralis is a rare finding in Spain. S. stercoralis simulates clinical findings of inflammatory bowel disease or eosinophilic gastroenteritis, which may lead to the wrong therapeutic choice. Since in inflammatory diseases corticosteroid treatments are considered the initial choice in many cases, in the case of S. stercoralis infection, the administration of this therapy can be fatal. In Spain, the number of diagnoses is much lower than in the past decade, although it is highly probable that the infection has been underdiagnosed due to low clinical awareness among Spanish population.

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A20 and ABIN-1 synergistically preserve intestinal epithelial cell survival

Journal of Experimental Medicine ◽

10.1084/jem.20180198 ◽

2018 ◽

Vol 215 (7) ◽

pp. 1839-1852 ◽

Cited By ~ 19

Author(s):

Michael G. Kattah ◽

Ling Shao ◽

Yenny Y. Rosli ◽

Hiromichi Shimizu ◽

Michael I. Whang ◽

...

Keyword(s):

Epithelial Cell ◽

Intestinal Epithelial Cell ◽

Kinase Activity ◽

Intestinal Inflammation ◽

Inflammatory Diseases ◽

Intestinal Epithelial ◽

Tissue Integrity ◽

Caspase Inhibition ◽

Inflammatory Bowel

A20 (TNFAIP3) and ABIN-1 (TNIP1) are candidate susceptibility genes for inflammatory bowel disease and other autoimmune or inflammatory diseases, but it is unclear how these proteins interact in vivo to prevent disease. Here we show that intestinal epithelial cell (IEC)-specific deletion of either A20 or ABIN-1 alone leads to negligible IEC loss, whereas simultaneous deletion of both A20 and ABIN-1 leads to rapid IEC death and mouse lethality. Deletion of both A20 and ABIN-1 from enteroids causes spontaneous cell death in the absence of microbes or hematopoietic cells. Studies with enteroids reveal that A20 and ABIN-1 synergistically restrict death by inhibiting TNF-induced caspase 8 activation and RIPK1 kinase activity. Inhibition of RIPK1 kinase activity alone, or caspase inhibition combined with RIPK3 deletion, abrogates IEC death by blocking both apoptosis and necroptosis in A20 and ABIN-1 double-deficient cells. These data show that the disease susceptibility proteins A20 and ABIN-1 synergistically prevent intestinal inflammation by restricting IEC death and preserving tissue integrity.

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Abstract P176: Proportionate Cardiovascular Mortality Patterns Among Patients With Inflammatory Disease In The United States, 1999-2018

Circulation ◽

10.1161/circ.143.suppl_1.p176 ◽

2021 ◽

Vol 143 (Suppl_1) ◽

Author(s):

Jacob Groenendyk ◽

Arjun Sinha ◽

Adovich Rivera ◽

Matthew J Feinstein

Keyword(s):

General Population ◽

Lupus Erythematosus ◽

The United States ◽

Morbidity Burden ◽

The Past ◽

Inflammatory Conditions ◽

Immunodeficiency Virus ◽

Control And Prevention ◽

Inflammatory Bowel ◽

Cvd Mortality

Introduction: Novel therapies have changed the clinical course of several chronic viral and inflammatory conditions over the past two decades. As the morbidity burden of these conditions has changed, competing risks for end-organ diseases including cardiovascular diseases (CVDs) may have likewise evolved. We therefore aimed to investigate changes in the relative burden of CVD mortality over the past two decades across several chronic infectious and inflammatory conditions. Hypothesis: Changes in proportionate CVD-related mortality over the past two decades differ across distinct infectious and inflammatory conditions. Methods: We analyzed 1999-2018 Multiple Causes of Death data from the Centers of Disease Control and Prevention. For several chronic infectious and inflammatory conditions, we analyzed patterns in age-adjusted cardiovascular proportionate mortality, defined as the fraction of deaths in a calendar year with CVD as the underlying cause. We compared age-adjusted proportionate CVD mortality, stratified by sex, for systemic lupus erythematosus (SLE), hepatitis C virus (HCV), human immunodeficiency virus (HIV), inflammatory bowel disease (IBD), psoriasis (PSO), rheumatoid arthritis (RA), and systemic sclerosis (SSc). Results: Proportionate CVD mortality in the general population decreased from 40.9% of 2319606 deaths (1999) to 30.6% of 2778169 deaths (2018), whereas it increased for chronic viral conditions (HCV: 7.0% to 10.2%; HIV: 1.9% to 6.7%) and changed little in SLE (15.3% to 14.4%). Patterns of decreasing proportionate CVD mortality over time were similar for IBD and RA as in the general population. Conclusions: Patterns in proportionate CVD mortality over the past 20 years vary considerably for different chronic infectious and inflammatory conditions. The underlying contributions of infectious and inflammatory burden, off-target effects of therapies, and dynamic changes in competing mortality risk merit further study.

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