Exaggerated Inflammatory Reaction Research Articles

Pediatric hemophagocytic lymphohistiocytosis: A rarely diagnosed entity in a developing country

BackgroundHemophagocytic lymphohistiocytosis (HLH) is an exaggerated inflammatory reaction secondary to a host’s inadequate immune response causing a self-perpetuating loop of altered regulation. Signs and symptoms of HLH are compatible with other common diseases and are nonspecific. Underdiagnosis makes it difficult to estimate the real incidence of HLH, especially in developing countries.MethodsRetrospective, descriptive study of pediatric patients admitted to a high-complexity institution in Cali, Colombia between 2012 and 2019 with HLH diagnosis. Medical history review to complete an electronic database and a secondary, descriptive analysis was carried out. The study was approved by the Institutional Ethics Committee.ResultsTwenty-one patients were included. 52.4 % of the population was male with a median age of 9.3 years [IQR (3.0-13.7 years)]. More than half of patients (66.6 %) had viral disease at diagnosis, the most frequent being Epstein-Barr Virus (EBV) (52.3 %) and dengue (14.3 %). Three patients had confirmed gene mutations (G6PC3, XIAP, and UNC13D). 95 % of the patients were treated with the HLH 2004 protocol, half of them received incomplete protocol with intravenous immunoglobulin (IVIG) and/or systemic steroids, while the other half received the complete protocol including etoposide and cyclosporine. More than three-fourths (76.2 %) required admission to an ICU with a median stay of 14 days [IQR (11–37 days)] and a median hospital stay of 30 days [IQR (18–93 days)]. 14.3 % (n = 3) of patients died.ConclusionsHLH is a complex disease that requires multidisciplinary management with secondary HLH due to EBV infection being a common cause. There is increasing awareness of HLH diagnosis in developing countries such as Colombia which can offer earlier treatment options and better outcomes.

COVID-19: Compreendendo a “tempestade de citocinas”

O SARS-CoV-2 espalhou-se rapidamente pela China e logo recebeu atenção mundial, levando a Organização Mundial da Saúde (OMS) a declarar, em 30 de janeiro de 2020, a infecção pelo SARS-CoV-2 como emergência de saúde pública de interesse internacional. Trata-se de uma revisão de literatura que objetiva atualizar e ampliar as informações disponíveis acerca do SARS-CoV-2, abrangendo a resposta imune contra ele e a consequente formação da tempestade de citocinas. Em alguns indivíduos, a resposta exacerbada do sistema imunológico provoca a hiperestimulação de suas células de defesa, causando uma hiperinflamação em decorrência da tempestade de citocinas pró-inflamatórias (TNF-α, IL-1-β, IL-6, IL-12 e quimiocinas). Essa hiperinflamação caracteriza a fisiopatologia da COVID-19 grave que provoca alterações patológicas principalmente nos pulmões, sendo um fator preditor de gravidade da doença devido à forte associação com a falência de múltiplos órgãos, podendo levar à morte. A dosagem dos níveis séricos de IL-6 e IL-10 foram considerados preditores da gravidade da doença e pode ser usada para o diagnóstico de pacientes com maior risco de agravamento da doença. Conclui-se que elevações dos níveis séricos de citocinas pró-inflamatórias geralmente estão presentes na COVID-19 grave. Porém, mais estudos são necessários para estabelecer diferenças entre os pacientes com COVID-19 que desenvolvem reação inflamatória protetora e equilibrada daqueles que desenvolvem reação inflamatória exagerada, com consequente tempestade patológica de citocinas.

Downregulation of calponin 2 contributes to the quiescence of lung macrophages.

Calponin 2 is an actin cytoskeleton-associated regulatory protein that inhibits the activity of myosin-ATPase and cytoskeleton dynamics. Recent studies have demonstrated that deletion of calponin 2 restricts the proinflammatory activation of macrophages in atherosclerosis and arthritis to attenuate the disease progression in mice. Here we demonstrate that the levels of calponin 2 vary among different macrophage populations, which may reflect their adaptation to specific tissue microenvironment corresponding to specific functional states. Interestingly, lung resident macrophages express significantly lower calponin 2 than peritoneal resident macrophages, which correlates with decreased substrate adhesion and reduced expression of proinflammatory cytokines and a proresolution phenotype. Deletion of calponin 2 in peritoneal macrophages also decreased substrate adhesion and downregulated the expression of proinflammatory cytokines. Providing the first line of defense against microbial invasion while receiving constant exposure to extrinsic antigens, lung macrophages need to maintain a necessary level of activity while limiting exaggerated inflammatory reaction. Therefore, their low level of calponin 2 may reflect an important physiological adaption. Downregulation of calponin 2 in macrophages may be targeted as a cytoskeleton-based novel mechanism, possibly via endoplasmic reticulum stress altering the processing and secretion of cytokines, to regulate immune response and promote quiescence for the treatment of inflammatory diseases.

Investigating unset endodontic sealers’ eugenol and hydrocortisone roles in modulating the initial steps of inflammation

Endodontic treatment success is achieved not only when the cement provides a hermetic seal but also when the injured periapical tissue is regenerated. However, an exaggerated inflammatory reaction hinders tissue regeneration and it has been shown that dental materials affect the inflammatory response through modulation of cytokine secretion. This work was set to investigate the effects of the presence of hydrocortisone in zinc oxide eugenol sealers (Endomethasone N) on modulating the initial steps of inflammation in vitro. Hydrocortisone and eugenol leaching from Endomethasone N and Pulp Canal Sealer (PCS) were quantified by ELISA and spectrofluorometry, respectively. The effects of Endomethasone N and Pulp Canal Sealer were studied on lipopolysaccharides (LPS)-stimulated human periodontal ligament (hPDL) cells. Cytokine (IL-6, TNF-α) secretion from cells was quantified by ELISA. Inflammatory cell (THP-1) adhesion to activated endothelial cells, their migration and activation were studied in vitro. Endomethasone N decreased secretion of IL-6 and TNF-α from hPDL cells. THP-1 adhesion to activated endothelial cells (HUVECs) and migration significantly decreased with Endomethasone N while no effect was observed with PCS. Activation of THP-1 decreased with both materials' extracts but was significantly lower with Endomethasone N than with PCS. These results performed in vitro show that Endomethasone N anti-inflammatory effects are due to the presence of hydrocortisone. Endomethasone N has potential local anti-inflammatory effects which appear to be due to its hydrocortisone rather than eugenol content. Decreasing the inflammatory response is a pre-requisite to initiate the periapical healing.

ANTI INFLAMMATORY EFFECT OF CIPROFLOXACIN, AZITHROMYCIN AND DICLOFENAC SODIUM ON CARRAGEENAN INDUCED HIND PAW EDEMA IN MICE

Background: Obviously, antibacterial agents are primarily directed against bacteria. However, because microorganisms can initiate an exaggerated inflammatory reaction, and as pathogens which persist in cryptic reservoirs (cells or granuloma tissue) can be the underlying cause of chronic inflammation, the hypothesis that antibacterials can down regulate inflammation. Methodology: Healthy adult mice weighing 20 - 30 g and aged 6-8 weeks, each group 6 mice were included. 1% carrageenan administered to produce inflammation. Grouping: Group 1: Normal saline 0.2 ml. i.p., Group 2: Diclofenac sodium 25mg/kg, Group 3 Ciprofloxacin 50 mg/kg, Group 4: Azithromycin 20mg/kg. Drugs were administered Intra Peritoneal. After 30 min of test drugs administration each group of mice were received subplantar administration of 0.05ml of saline (Control) or 0.05ml carrageenan (1%) for test groups 2 to 4. Paw volumes were measured by dipping in to the mercury plethysmograph at 30, 60, 120 and 180 minutes and results were tabulated. Results: Diclofenac, ciproflaoxin, Azithromycin inhibited paw edema in % at 30min 42.85, 28.55, 14.28, at 60min 75, 50, 25, at 120min 71.42, 42.85, 14.28, and at 180 min 50, 50, 25 respectively. Conclusion: Ciprofloxacin (50mg/kg) has exhibited consistent anti-inflammatory, but the anti-inflammatory activity of is less than that of Diclofenac sodium and Azithromycin also has exhibited anti-inflammatory activity, though much less when compared to Diclofenac sodium and Ciprofloxacin. Key words: Anti inflammatory effect; Azithromycin; Ciprofloxacin; Diclofenac Sodium; Paw edema; Mice.

Immune system's role in viral encephalitis

Viral infections can be a major thread for the central nervous system (CNS), therefore, the immune system must be able to mount a highly proportionate immune response, not too weak, which would allow the virus to proliferate, but not too strong either, to avoid collateral damages. Here, we aim at reviewing the immunological mechanisms involved in the host defense in viral CNS infections. First, we review the specificities of the innate as well as the adaptive immune responses in the CNS, using several examples of various viral encephalitis. Then, we focus on three different modes of interactions between viruses and immune responses, namely human Herpes virus-1 encephalitis with the defect in innate immune response which favors this disease; JC virus-caused progressive multifocal leukoencephalopathy and the crucial role of adaptive immune response in this example; and finally, HIV infection with the accompanying low grade chronic inflammation in the CNS in some patients, which may be an explanation for the presence of cognitive disorders, even in some well-treated HIV-infected patients. We also emphasize that, although the immune response is generally associated with viral replication control and limited cellular death, an exaggerated inflammatory reaction can lead to tissue damage and can be detrimental for the host, a feature of the immune reconstitution inflammatory syndrome (IRIS). We will briefly address the indication of steroids in this situation.

Macrophage Activation Syndrome in a Child Affected by Malaria: The Choice of Steroid

Macrophage activation syndrome is a potentially fatal clinical syndrome caused by an excessive activation and proliferation of macrophages and T cells, leading to an exaggerated inflammatory reaction. It is well known that it can complicate the course of different conditions, especially autoimmune, lympho-proliferative, infectious diseases and drugs. Many infective pathogens can trigger the syndrome but the association with malaria has rarely been described, especially in children. We report a child with severe malaria complicated by MAS, in whom the clinical appearance of this syndrome could be considered as worsening of malaria itself. Furthermore, the use of steroids as first choice drugs in this complication, but arguable in malaria, has been highlighted. Clinicians should be aware of this syndrome when malaria does not respond to conventional therapy, since early diagnosis and prompt treatment may dramatically reduce the mortality associated with this condition.

The innate immune response in reperfused myocardium

One of the major therapeutic challenges in the arena of interventional cardiology is to design strategies aimed at reducing myocardial tissue damage after myocardial infarction. In response to tissue injury, an innate immune response is initiated that orchestrates homeostatic responses and is a prerequisite for subsequent wound healing. An exaggerated inflammatory reaction, however, countervenes these beneficial effects and contributes to maladaptive tissue damage. Herein, we discuss the pathways involving the innate immune system that have been investigated in the setting of myocardial ischaemia and reperfusion injury. Endogenous 'danger' signals [danger-associated molecular patterns (DAMPs)] are expressed following tissue injury and alert the innate immune system. Toll-like receptors and the complement system are activated, resulting in an inflammatory reaction involving inflammatory cell influx and the production and release of inflammatory cytokines. A potential involvement of cell-derived microparticles in the modulation of the innate immune response following myocardial injury will also be discussed. Our future challenge lies within the counteraction of maladaptive inflammatory cascades, without interfering in the benign wound healing response, and in translating these anti-inflammatory strategies into clinical practice.

Inflammatory Response to Therapeutic Gold Bead Implantation in Canine Hip Joint Osteoarthritis

Inflammatory changes associated with periarticular pure gold bead implants were studied in dogs involved in a clinical trial investigating motor dysfunction and chronic pain owing to hip joint dysplasia and osteoarthritis. Gold beads were percutaneously implanted via a needle into different locations surrounding the greater trochanter of the femur. Nine dogs with implants were necropsied. In all examined animals, characteristic histologic lesions were observed in the tissue surrounding the gold implants--namely, a fibrous capsule composed of concentric fibroblasts intermixed with a variable number of inflammatory cells and a paucicellular innermost layer of collagen with a few fibrocyte-like cells in empty lacunae. Lymphocytes dominated the inflammatory infiltrate, with rarely observed macrophages present in close proximity to the implant site. No giant cells were observed. Immunohistochemistry showed mixed populations of lymphocytes, both CD3 positive (T cells) and CD79a positive (B cells), which in some cases formed lymphoid follicles. Diffuse inflammatory changes were present to a minor extent in the perimysium and surrounding fascia. The inflammation observed in dogs is similar to that observed with gold implants in humans. It is possible that the clinically beneficial effect of gold beads for chronic osteoarthritis depends on sustained localized inflammation with localized release of soluble mediators. The encapsulation of the implant by a paucicellular and poorly vascularized fibrous capsule may help prevent an exaggerated inflammatory reaction by sequestering the gold bead from the surrounding tissue.

Pathophysiologie der Entzündung und ernährungsmedizinische Intervention

Die Prävalenz der Autoimmunerkrankungen steigt in den Industrienationen während der letzten Jahre ständig an. Pathophysiologisch sind Autoimmunerkrankungen durch eine gesteigerte Entzündungsreaktion gekennzeichnet, die infolge des persistierenden Antigens perpetuiert. Proinflammatorische Mediatoren, die als Cytokine, Chemokine und Eicosanoide miteinander interagieren, werden überschießend gebildet. Die Forschung der letzten 20 Jahre hat gezeigt, dass das Eicosanoidsystem ernährungsabhängig beeinflusst werden kann. Arachidonsäure wird mit der in Industrienationen üblichen hohen Fleischzufuhr exzessiv zugeführt und ist die Ausgangssubstanz proinflammatorischer Eicosanoide. Eicosapentaensäure und die aus ihr gebildeten Eicosanoide wirken entzündungshemmend. Wegen des geringen Fischverzehrs überwiegen in den Industrienationen die proinflammatorischen Stimuli. Möglicherweise ist dies auch ein Grund für das gehäufte Auftreten der Autoimmunerkrankungen und anderer Erkrankungen mit gesteigerter Eicosanoidbiosynthese in den Industrienationen.

Mast cell: pivotal player in lethal acute pancreatitis.

The fearful aura of acute pancreatitis stems from the imagery of an organ and organism under threat of cannibalization by pancreatic enzymes that have become active prematurely. This century‐old autodigestion theory1 is all too plausible when one is confronted with the necrohaemorrhagic remains of the gland in a patient who succumbs from multisystem organ failure, as do 10–20% of cases. It was challenged2 when the average interval from onset of symptoms to death was found to be shorter (under 48 h) and the degree of initial shock greater with interstitial pancreatitis—which accounts for a quarter of the toll3—than with wholesale coagulative necrosis, an infarct‐like lesion associated with hyaline occlusion of venules and capillaries.2 The literature is colossal—4844 titles in a Medline search from 1966, and 260 in 1999—but the current position can be gleaned from a recent monograph,4 an assortment of reviews5–,11 and supplementary papers. Of necessity, much reliance has been placed on studies of experimental pancreatitis to unravel the earliest aberrations. From these and clinical studies, it is now believed that the ‘attack’ begins in the acinar cell, with a functional blockade in the secretory pathway towards exocytosis of zymogen granules. It is also agreed that multiorgan collapse is primarily due to hyperinflammation, abetted by activation of coagulation, fibrinolytic, kallikrein‐kinin and complement enzyme cascades with consumption of α2 macroglobulin (α2M). The debate concerns the nature of the trigger mechanism and why it should evoke an exaggerated inflammatory reaction and cause (subclinical) disturbances in distant organs even when the disease seems to be mild. In the latter context, the injured acinar cell is now known to step up its production of platelet‐activating factor (PAF)—a physiological secretagogue but which at high doses inhibits secretion—and to synthesize heat‐shock and acute‐phase proteins, …