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Persistent inflammation is the key aggravator in many cardiovascular diseases, including atherosclerosis, aneurysm, injury/reperfusion, thrombosis, and neointimal hyperplasia following surgical or percutaneous interventions. Resolution is an active process orchestrated by specialized pro-resolving lipid mediators (SPMs) which tamp down acute inflammatory signals, promote healing and facilitate a return to homeostasis. SPMs are endogenously derived from poly-unsaturated fatty acids, and their biologic activity is mediated via specific G-protein coupled receptor binding. The potency of SPM in regulating the inflammatory response has encouraged investigation into their therapeutic and diagnostic use in cardiovascular pathologies. Herein we describe the translational groundwork which has established the synthesis and interactions of SPM in cardiovascular and hematologic cells, the therapeutic effects of SPM in animal models of cardiovascular disease, and some early technologies that harness and attempt to optimize SPM delivery and "resolution pharmacology". Further studies are required to precisely determine the mechanisms of resolution in the cardiovascular system and to determine the clinical settings in which SPM can be utilized to optimize patient outcomes.

As early as the 1990s, chronic critical illness, a distinct syndrome of persistent high-acuity illness requiring management in the ICU, was reported under a variety of descriptive terms including the "neuropathy of critical illness," "myopathy of critical illness," "ICU-acquired weakness," and most recently "post-intensive care unit syndrome." The widespread implementation of targeted shock resuscitation, improved organ support modalities, and evidence-based protocolized ICU care has resulted in significantly decreased in-hospital mortality within surgical ICUs, specifically by reducing early multiple organ failure deaths. However, a new phenotype of multiple organ failure has now emerged with persistent but manageable organ dysfunction, high resource utilization, and discharge to prolonged care facilities. This new multiple organ failure phenotype is now clinically associated with the rapidly increasing incidence of chronic critical illness in critically ill surgery patients. Although the underlying pathophysiology driving chronic critical illness remains incompletely described, the persistent inflammation, immunosuppression, and catabolism syndrome has been proposed as a mechanistic framework in which to explain the increased incidence of chronic critical illness in surgical ICUs. The purpose of this review is to provide a historic perspective of the epidemiologic evolution of multiple organ failure into persistent inflammation, immunosuppression, and catabolism syndrome; describe the mechanism that drives and sustains chronic critical illness, and review the long-term outcomes of surgical patients who develop chronic critical illness.

Skin chronic wounds are associated with a state of persistent inflammation and often with infection, originating a specific microenvironment characterized by increased temperature, alkaline pH, elevated enzymatic activity, and high levels of reactive oxygen species (ROS). These alterations can be explored as intrinsic triggers in the design of stimuli-responsive biomaterials for the release of bioactive molecules at the wound microenvironment. Stimuli-responsive biomaterials may not only prolong the bioactivity of the therapeutic agents but also synchronize it with the healing stages, tuning the wound treatment. In addition, the high activity of enzymes, such as lysozyme in infected chronic wounds, as well as the shift to a more alkaline pH may be used as biomarkers for early detection of infected and/or non-healing wounds. Overall, although a few shortcomings still need to be addressed before clinical translation, the bioengineered smart formulations highlighted in this review stand out as a new generation of therapies to manage skin chronic wounds. This work was supported by Portuguese funds through FCT-MCTES (Fundação para a Ciência e Tecnologia and Ministério da Ciência, Tecnologia e Ensino Superior) through the project “AntINFECT“ (POCI-01-0145-FEDER-031781, PTDC/NAN-MAT/31781/2017). FCT-MCTES is further acknowledged for funding LAQV-REQUIMTE Research Unit (UIDB/50006/2020). P.A. thanks FCT-MCTES for the doctoral grant SFRH/BD/145471/2019 financially supported by national and European Union funds (ESF – European Social Fund through “Programa Operacional Regional Norte”).

Traumatic brain injury (TBI) is one of the leading causes of disability and mortality of people at all ages. Biochemical, cellular and physiological events that occur during primary injury lead to a delayed and long-term secondary damage that can last from hours to years. Secondary brain injury causes tissue damage in the central nervous system and a subsequent strong and rapid inflammatory response that may lead to persistent inflammation. However, this inflammatory response is not limited to the brain. Inflammatory mediators are transferred from damaged brain tissue to the bloodstream and produce a systemic inflammatory response in peripheral organs, including the cardiovascular, pulmonary, gastrointestinal, renal and endocrine systems. Complications of TBI are associated with its multiple and systemic effects that should be considered in the treatment of TBI patients. Therefore, in this review, an attempt was made to examine the systemic effects of TBI in detail. It is hoped that this review will identify the mechanisms of injury and complications of TBI, and open a window for promising treatment in TBI complications.

To explore clinical characteristics and long-term quality of life (QOL) in severe acute pancreatitis (SAP) patients with persistent inflammation-immunosuppression and catabolism syndrome (PICS).SAP patients admitted to ICU were eligible for the retrospective cohort study if they needed prolonged intensive care (14days). Post-ICU QOL was assessed by a questionnaire, including 36-item Short Form Health Survey (SF-36) and record of re-work in a long-term follow-up.214 SAP patients were enrolled, in which 149 (69.6%) patients met the criteria of PICS. PICS patients had more complications and ICU days compared to non-PICS patients (P0.001), and their post-ICU mortality was higher (P=0.046). When adjusted for confounders, PICS was independently associated with higher post-ICU mortality (hazard ratio 4.5; 95% CI, 1.2 to 16.3; P=0.024). The 36-item Short Form Health Survey (SF-36) score was lower for PICS group in six subscales (P0.001). Only 28.8% patients in the PICS group returned to work compared to 60% patients in the non-PICS group (P=0.001) CONCLUSIONS: SAP patients with prolonged ICU stay had a high morbidity of PICS, which was a risk factor for the post-ICU mortality and poor long-term QOL.

Summary Inflammation, an essential tissue response to extrinsic/intrinsic damage, is a very dynamic process in terms of complexity and extension of cellular and metabolic involvement. The aim of the inflammatory response is to eliminate the pathogenic initiator with limited collateral damage of the inflamed tissue, followed by a complex tissue repair to the preinflammation phenotype. Persistent inflammation is a major contributor to the pathogenesis of many musculoskeletal diseases including ageing-related pathologies such as osteoporosis, osteoarthritis, and sarcopaenia. The translational potential of this article : Understanding the mechanisms of inflammation and its resolution is therefore critical for the development of effective regenerative, and therapeutic strategies in orthopaedics.

Stevens-Johnson syndrome (SJS) is an acute blistering disease of the skin and mucous membranes. Acute SJS leads to the acute inflammation of the ocular surface and chronic conjunctivitis. If not properly treated, it causes chronic cicatricial conjunctivitis and cicatricial lid margin abnormalities. Persistent inflammation and ulceration of the ocular surface with cicatricial complications of the lids leads to chronic ocular sequelae, ocular surface damage, and corneal scarring. The destruction of the glands that secrete the tear film leads to a severe form of dry eye that makes the management of chronic SJS difficult. The option that is routinely used for corneal visual rehabilitation, keratoplasty, is best avoided in such cases. We describe the management strategies that are most effective during the acute and chronic stages of SJS. Although treatments for acute SJS involve immunosuppressive and immunomodulatory therapies, amniotic membrane transplantation is also useful. The options for visual rehabilitation in patients with chronic SJS are undergoing radical change. We describe the existing literature regarding the management of SJS and highlight recent advances in the management of this disorder.

Objectives To better understand the effect of TNF-α inhibitors (TNFi) on new bone formation in ankylosing spondylitis (AS) patients. Methods We systematically searched the articles in EMBASE and PubMed. Results Fifteen articles were enrolled. In all the 9 TNFi-treated cohorts, the vertebral corners with inflammatory lesions at baseline were at higher risk to develop new syndesmophytes than those without inflammatory lesions, although a few syndesmophytes also developed at the vertebral corners without inflammatory lesions at baseline. The advanced inflammatory lesions including fat deposition on baseline MRI showed a higher risk for syndesmophyte formation than the acute inflammatory lesions. Because the number of analyzed vertebral corners were too small, it might not be true that new syndesmophytes developed more frequently at the corners with inflammatory lesions completely resolved than those with persistent inflammation after TNFi treatment. Four studies with 2-year follow-up revealed null effect of TNFi on radiographic progression compared with historical controls with lower disease activity, and 3 studies with ≥ 4-year follow-up proved inhibitory effect of TNFi on new bone formation in AS patients. Patients with a delay of > 10 years in starting TNFi therapy were more likely to experience radiographic progression as compared to those who started earlier. Conclusions In TNFi treated AS patients, baseline inflammation is linked with syndesmophyte development. An earlier initiation of TNFi therapy may slow the radiographic progression in AS, and TNFi may lose its benefit of retarding new bone formation at advanced stage of AS especially after the focal fat infiltration or syndesmophyte formation.

Macrophages are key players in wound healing- along with mediating the acute inflammatory response, macrophages activate cutaneous epithelial cells and promote tissue repair. Diabetes complications, including diabetic chronic wounds, are accompanied by persistent inflammation and macrophage malfunction. Several studies indicate that hyperglycemia induces various alterations that affect macrophage function in wound healing including epigenetic changes, imbalance between pro- and anti-inflammatory modulators, and insensitivity to proliferative stimuli. In this review, we briefly summarize recent studies regarding those alterations and their implications on skin well-being in diabetes.

In the work presented here, a novel mathematical model was developed to explore the bi-directional communication between the hypothalamic-pituitary-adrenal (HPA) axis and inflammatory cytokines in acute inflammation. The dynamic model consists of five delay differential equations 5D for two main pro-inflammatory cytokines (TNF-α and IL-6) and two hormones of the HPA axis (ACTH and cortisol) and LPS endotoxin. The model is an attempt to increase the understanding of the role of primary hormones and cytokines in this complex relationship by demonstrating the influence of different organs and hormones in the regulation of the inflammatory response. The model captures the main qualitative features of cytokine and hormone dynamics when a toxic challenge is introduced. Moreover, in this work a new simple delayed model of the HPA axis is introduced which supports the understanding of the ultradian rhythm of HPA hormones both in normal and infection conditions. Through simulations using the model, the role of key inflammatory cytokines and cortisol in transition from acute to persistent inflammation through stability analysis is investigated. Also, by employing a Markov chain Monte Carlo (MCMC) method, parameter uncertainty and the effects of parameter variations on each other are analyzed. This model confirms the important role of the HPA axis in acute and prolonged inflammation and can be a useful tool in further investigation of the role of stress on the immune response to infectious diseases.

The goal of treating chronic inflammatory diseases must be to inhibit persistent inflammation and restore tissue function. To achieve this we need to improve our understanding of the pathways that drive inflammation as well as those that bring about its resolution. In particular, resolution of inflammation is driven by a complex set of mediators that regulate cellular events required to clear inflammatory cells from sites of injury or infection and restore homeostasis. Indeed, it may be argued that dysfunctional resolution may underpin the aetiology of some chronic inflammatory disease and that a novel goal in treating such diseases is to develop drugs based on the mode of endogenous pro-resolution factors in order to drive on-going inflammation down a pro-resolution pathway. And while we are improving our understanding of the resolution of acute and chronic inflammation, much remains to be discovered. Here we will discuss the key endogenous checkpoints necessary for mounting an effective yet limited inflammatory response and the crucial biochemical pathways necessary to prevent its persistence and trigger its resolution. In doing so, we will provide an update on what is known about resolution of acute inflammation, in particular its link with adaptive immunity.

Elite controllers naturally suppress HIV viraemia below the level of detection using standard methods, but demonstrate persistent inflammation and low-level viraemia that is detectable via ultrasensitive assays. These factors may contribute to an increased risk of non-AIDS-related morbidity and mortality among elite controllers. Data suggest that cardiovascular disease may be of particular concern in elite controllers, as evidenced by an increased burden of subclinical cardiovascular disease upon radiographic screening and an elevated rate of hospitalisations for cardiovascular disease as compared to non-controllers who are treated with antiretroviral therapy (ART). Widespread use of ART among non-controllers has led to significant declines in morbidity and mortality, but guidelines are generally silent on the role of ART in the care of elite controllers. Multiple small studies have demonstrated that laboratory markers of inflammation, immune activation and HIV burden improve after initiation of ART in elite controllers. Clinicians must consider these potential benefits of ART when deciding whether to initiate treatment in asymptomatic elite controllers.

The development and severity of ARDS are closely related to dysregulated inflammation, and the duration of ARDS and eventual outcomes are related to persistent inflammation and abnormal fibroproliferation. Corticosteroids are potent modulators of inflammation and inhibitors of fibrosis that have been used since the description of the acute respiratory distress syndrome in attempts to improve outcomes. Randomized controlled trials of steroids for ARDS have answered some, but not all, questions regarding efficacy for prevention and treatment. First, there is no evidence that corticosteroids prevent the development of ARDS among patients at risk. Second, high dose and short course treatment with steroids does not improve the outcomes of patients with ARDS. And third, while there is compelling data that low dose and prolonged treatment with steroids improves pulmonary physiology in patients with ARDS, additional studies are needed to recommend treatment with steroids for ARDS.

Great strides have been made in understanding the epidemiology of EoE over the past two decades. Initial research focused on case description and characterization of the burden of disease. Research is now shifting to risk factor ascertainment, resulting in new and intriguing etiologic hypotheses. This paper will review the current knowledge related to the epidemiology of EoE. Demographic features and natural history will be described, data summarizing the prevalence and incidence of EoE throughout the world will be highlighted, and risk factors for EoE will be discussed. EoE can occur at any age, there is a male predominance, it is more common in Whites, and there is a strong association with atopic diseases. EoE is chronic, relapses are frequent, and persistent inflammation increases the risk of fibrostenotic complications. The prevalence is currently estimated at 0.5–1 in 1000, and EoE is now the most common cause of food impaction. EoE can be seen in 2–7% of patients undergoing endoscopy for any reason, and 12–23% undergoing endoscopy for dysphagia. The incidence of EoE is approximately 1/10,000 new cases per year, and the rise in incidence is outpacing increases in recognition and endoscopy volume. The reasons for this evolving epidemiology are not yet fully delineated, but possibilities include changes in food allergens, increasing aeroallergens and other environmental factors, the decrease of H. pyloriand early life exposures.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatological disease of childhood. Despite the current availability of potent disease-modifying anti-rheumatic medications, most children still experience a chronic course with prolonged periods of active disease. Goals for treatment should include disease remission with optimal physical functioning allowing children to lead normal lives without structural joint damage. However, recent studies demonstrate only moderate rates of remission, indicating that JIA is not as benign as previously thought. The probability of attaining remission within 5 years is approximately 50% across all JIA categories except for polyarthritis when the outlook is significantly worse. Longer term, about 50% of adults with JIA suffer from persistent inflammation and disability. There is a shift towards early aggressive treatment with the intention to switch off inflammation since there may be a ‘window of opportunity' before the disease becomes chronic. There is clear evidence for improved outcome in adult patients treated with this approach (‘treat to target') but limited paediatric evidence to date. The explosion in anticytokine agents for treatment of disease resistant to conventional therapy has expanded our armamentarium, improving short term clinical outcomes, but it is still unclear whether we have achieved significant improvements in outcome longer term. This review describes the disease and current and longer-term data on outcomes for this common chronic childhood condition.

Previous studies have reported the clinical outcomes of the Zilver PTXTM, a paclitaxel-eluting nitinol stent (Cook® Medical, Bloomington, IN, USA), in patients with de novo or restenotic lesions of the femoropopliteal artery. Intravascular optical coherence tomography (OCT) provides imaging of

Although endometritis is a normal occurrence after breeding, persistent inflammation threatens the success of the pregnancy. Persistent endometritis has been cited as a leading reproductive health concern in the mare. A variety of factors contribute to susceptibility to persistent breeding induced endometritis, including age, endometrial quality, and reproductive history. Seminal plasma mediates the immune response to breeding, as it has protective properties for viable spermatozoa, while aiding in the recognition and targeting of dead spermatozoa by the mare's immune response. Although the adaptive immune response has been implicated in the response to breeding, the innate immune response along with mechanical clearance are the primary mechanisms suggested to act to clear endometritis. Mares susceptible to persistent breeding induced endometritis have an altered innate immune response after breeding compared to resistant mares. There are multiple tools and strategies utilized for the diagnosis and treatment of persistent endometritis. This review of the literature summarizes research investigating the causes, pathogenesis, and treatments of persistent breeding induced endometritis.

Chronic pancreatitis is a persistent inflammation of the pancreas that results in irreversible morphological changes and impairment of both exocrine and endocrine functions. Genetic studies of the disease over the past 15 years have led to the identification of four firmly established susceptibility genes namely PRSS1, SPNIK1, CTRC and CFTR. Our previously published review (Chen and Férec. Annu Rev Genomics Hum Genet 2009) has comprehensively summarized the advances made in terms of genetics and pathogenesis of chronic pancreatitis, covering the data available up to early 2009. This review summarizes the important and representative findings published thereafter, focusing on (i) newly found disease-causing mutations, (ii) functional characterization of known variations and (iii) genotype and phenotype relationship.

Autoinflammatory syndromes are characterised by recurrent or persistent inflammation with no increase in the antibody titers or antigen-specific T lymphocytes, and absence of infection. Initially, they included the hereditary periodic fever syndromes, a group of innate immune system monogenic diseases characterised by recurrent febrile episodes, with different characteristics, duration and interval, accompanied by other symptoms. Secondary amyloidosis is a complication in this group. The advances in the last few years has led to the identification of susceptible genes, new proteins, and characterising mechanisms and pathogenic routes that have led to an improvement in the diagnosis and establishing more effective treatments. Among these routes, are the changes in the inflammasome components, a group of cytoplasmic proteins that regulate the production of several inflammatory response mediators. The initial group of monogenic autoinflammatory diseases have increased in the last few years, due to including several polygenic hereditary diseases.

The increased risk of late ischemic events with drug eluting stents (DES) may, in part, be due to persistent inflammation and delayed vascular healing induced by their durable polymer (DP) coating. Biodegradable-polymer (BP-) and polymer-free (PF-) DES were developed in an attempt to mitigate this

Chronic constrictive pericarditis: MR imaging features Chronic constrictive pericarditis is defined by an increase in the rigidity of the pericardium resulting in impairment of the ventricular filling conditions. Cardiac MR is both a morphological and functional study always complemented by multi-detector CT. Morphological analysis is based on axial, longitudinal long axis and short axis views on Turbo (fast) SE Dark Blood and CINE sequences. Functional analysis is based on real-time acquisitions in the short axis at the base of the ventricles by comparing spontaneous breathing and deep breathing. The excursion of the interventricular septum is a reliable sign of constriction. The study is supplemented by phase contrast acquisitions. In the setting of persistent inflammation or free pericardial fluid, delayed enhancement 3D and 2D sequences including Phase Sensitive Inversion Recovery (PSIR ® ) are useful.

The increased risk of late ischemic events with drug eluting stents (DES) may, in part, be due to persistent inflammation and delayed vascular healing induced by their durable polymer (DP) coating. Biodegradable-polymer (BP-) and polymer-free (PF-) DES were developed in an attempt to mitigate this

We have so far reported that atomic bomb (A-bomb) survivors have persistent subclinical inflammation. This study reports on the analysis of persistent inflammation among A-bomb survivors with respect to sex and age at the time of the bombings. Among 6258 A-bomb survivors undergoing seven inflammatory tests, standardized inflammatory scores, used as inflammation indices for each person, were regressed for city, age at examination, age at the time of the bombings, inflammatory diseases, smoking, and radiation dose, in order to analyze the effects of radiation dose. The results indicate that the inflammation scores increased significantly for both males and females younger than 20 years old at the time of bombings, while the scores increased significantly only for the females that were 20 years old or older at the time of the bombings. As evidence has been observed, on the one hand in the radiosensitive young generation, and on the other hand in the population with a high risk of radiation-induced disorders in the estrogen receptor organs, such as thyroid cancer, breast cancer, ovarian cancer and uterine myoma, a close association between the persistent inflammation and the radiation damage mechanism(s) is suggested.

The simplistic view of atherosclerosis as a disorder of pathologic lipid deposition has been redefined by the more complex concept of an ongoing inflammatory response ([1][1]). Several cellular components seem to participate in this persistent inflammation, such as macrophages, vascular smooth

Summary Our knowledge of the mechanisms which sustain the allergic reaction has improved rapidly, revealing a complex network of cells, mediators and cytokines. The intercellular adhesion system (and the ICAM-1 molecule in particular) appeared to play a pivotal role in the recruiting and accumulation of inflammatory cells at the site of allergic reaction. The role of CAMs in the allergic inflammation have been clearly elucidated by means of the specific nasal and conjunctival challenge which represent an interesting and reliable model. Using these in vivo models, some of the dynamic aspects of the allergic inflammation have been clarified and the existence of a minimal persistent inflammation in symptom free subjects has been also described. The accumulated experience suggested the need for a different therapeutical approach to the treatment of allergy i.e. long-term and early treatments, in order to achieve not only the control of the symptoms, but also of the allergic inflammation. Moreover, the in vivo studies evidenced the possibility of modulating by drugs the expression of adhesion molecules, thus suggesting new therapeutical approaches for the treatment of allergic diseases.

As a result of shaping, finishing, or removal of dental composite resin restorations, resin particles may become trapped and embedded in oral tissues. However, tissue reactions induced by entrapped composite resin particles have not been thoroughly examined. To assess the soft tissue inflammatory response to composite restorative materials, three commercial dental composite resin suspensions were implanted subcutaneously in rats. Implantation resulted in a granulornatous inflammatory reaction that persisted S weeks after placement. The lesion was characterized by an influx of lymphocytes and the presence of fabroblasts and epithelioid cells. Composite resin particles have the potential to cause persistent inflammation if they are entrapped in oral tissues.

Bioresorbable polymer coatings are hoped to minimize persistent inflammation associated with durable polymer usage as a drug carrier in drug-eluting stents (DES). We examined the time course of para-strut inflammation (PI) of 3 contemporary DES featuring abluminal bioresorbable polymer coating (

The limited restorative capacity of mammalian tissues has been attributed to the loss of adequate cell replacement coupled with persistent inflammation with increasing age. Using mouse genetics we have investigated the role of growth factors and resident cells in the resolution of tissue injury. We have uncovered a complex interaction between local repair mechanisms and cells of the innate immune system, which participate in the removal of necrotic cells, secrete growth factors that limit inflammation and promote tissue replacement, and also act as tissue stem cells in the repair process. Our work supports the feasibility of improving mammali ets for clinical intervention and improving prospects for molecular and cellular combination therapies.an regenerative capacity by modulating key signaling pathways controlled by these cells, providing new targ

There is a vigorous change in cytokine response in individuals with HIV infection. Although this is mitigated by highly active antiretroviral therapy (HAART) and natural control of virus, cytokine levels remain perturbed. To identify and investigate serum cytokines that may play a role in control of viremia or immune-related pathogenesis, we compared four groups from the Women’s Interagency HIV Study defined by HIV clinical status: ELITE controllers (viral load

Progressive external inflammatory root resorption, a result of persistent inflammation within the periodontal membrane, will cause eventual destruction of the tooth root if the inflammation is not eradicated. This study examined the effects of an antibiotic/corticosteroid paste on experimental inflammatory resorption induced in monkeys in vivo. Histologic evaluation of results with the use of a morphometric technique revealed that the paste eliminated inflammatory root resorption and had no damaging effects upon the periodontal membrane. It was concluded that this antibiotic/corticosteroid combination is an effective medication for use in the treatment of progressive root resorption in traumatically injured teeth.

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