Role Of Inflammatory Mediators Research Articles

Hemin-induced necroptosis involves glutathione depletion in mouse astrocytes

Intracerebral hemorrhage (ICH) is a devastating neurological injury associated with significant mortality. Astrocytic inflammation may contribute to the pathogenesis of ICH, although the underlying cellular mechanisms remain unclear. In this study, the hemoglobin oxidation by-product, hemin, concentration-dependently induced necroptotic cell death in cortical astrocytes within 5 h of treatment. Hemin-induced cell death was preceded by increased inflammatory gene expression (COX-2, IL-1β, TNF-α, iNOS). Inhibition of the NF-κB transcription factor reversed inflammatory gene expression and attenuated cell death after hemin treatment, suggesting a possible role for inflammatory mediators in astrocytic injury. Superoxide production paralleled the increase in iNOS expression, and inhibition of either iNOS (aminoguanidine or iminopiperdine) or superoxide (apocynin) significantly reduced cell death. Similarly, reduced formation of peroxynitrite, the damaging product of nitric oxide and superoxide, significantly reduced hemin injury. Hemin-induced peroxidative injury was associated with a rapid depletion of intracellular glutathione (GSH), culminating in lipid peroxidation and cell death, effects that were reduced by cotreatment with exogenous GSH, N-acetyl- l-cysteine, or the glutathione peroxidase mimetic ebselen. Together, these studies suggest a novel role for GSH depletion in necroptotic astrocyte injury after a hemorrhagic injury and indicate that therapeutic targeting of GSH may exert a beneficial effect after ICH.

Chemokines and Bone Remodeling

Bone remodeling is characterized by spatial and temporal coupling of bone resorption and formation and is necessary for skeletal growth and normal bone structure maintenance. Imbalance of this process is related to metabolic bone disorders such as osteoporosis or rheumatoid arthritis. For this reason, bone remodeling is under the control of several local and systemic factors, including molecules of the immune system. The importance of the interplay of both the skeletal and immune systems is reflected by the emerging interdisciplinary research field, called osteoimmunology, focused on common aspects of osteology and immunology. This review focuses on the role of inflammatory mediators, such as cytokines in bone remodeling and, in particular, a subfamily of chemotactic cytokines or chemokines which are involved not only in several aspects of physiological bone remodeling but also in pathological bone disorders, such as rheumatoid arthritis or osteoporosis. Understanding the role of inflammation and chemokines will provide new insights for the treatment of diseases affecting both skeletal and immune systems, by the development of new therapeutic strategies targeting common inflammatory mediators.

A Review of Cardiogenic Shock in Acute Myocardial Infarction

Cardiogenic shock continues to be the most common cause of death in patients hospitalized with acute myocardial infarction. It has also been frequently associated with ST-segment elevation myocardial infarction (STEMI) and patients with co-morbidities. Cardiogenic shock presents with low systolic blood pressure and clinical signs of hypoperfusion. Rapid diagnosis and supportive therapy in the form of medications, airway support and intra-aortic balloon counterpulsation is required. Initial stabilization can be followed by reperfusion by fibrinolytic therapy, emergent percutaneous intervention (PCI) or coronary artery bypass grafting (CABG). The latter two have been found to decrease mortality in the long term. Research is being carried out on the role of inflammatory mediators in the clinical manifestation of cardiogenic shock. Mechanical support devices also show promise in the future.

The Role of Inflammatory Mediators in the Pathogenesis of Otitis Media and Sequelae

This review deals with the characteristics of various inflammatory mediators identified in the middle ear during otitis media and in cholesteatoma. The role of each inflammatory mediator in the pathogenesis of otitis media and cholesteatoma has been discussed. Further, the relation of each inflammatory mediator to the pathophysiology of the middle and inner ear along with its mechanisms of pathological change has been described. The mechanisms of hearing loss including sensorineural hearing loss (SNHL) as a sequela of otitis media are also discussed. The passage of inflammatory mediators through the round window membrane into the scala tympani is indicated. In an experimental animal model, an application of cytokines and lipopolysaccharide (LPS), a bacterial toxin, on the round window membrane induced sensorineural hearing loss as identified through auditory brainstem response threshold shifts. An increase in permeability of the blood-labyrinth barrier (BLB) was observed following application of these inflammatory mediators and LPS. The leakage of the blood components into the lateral wall of the cochlea through an increase in BLB permeability appears to be related to the sensorineural hearing loss by hindering K+ recycling through the lateral wall disrupting the ion homeostasis of the endolymph. Further studies on the roles of various inflammatory mediators and bacterial toxins in inducing the sensorineumral hearing loss in otitis media should be pursued.

Drug Disease Interactions: Role of Inflammatory Mediators in Pain and Variability in Analgesic Drug Response

Pain has both physical and emotional components. Physical noxious stimuli activate peripheral sensory neurons that, in turn, relay signals to the spinal and supraspinal nuclei. Subsequently, these signals activate areas within the brain associated with pain. Despite considerable knowledge in this area, analgesics may provide pain complete relief in only one out of five patients. Failure to manage pain may be due to a lack of understanding of the neurobiological processing of pain. Factors such as anticipation, anxiety and pain history play roles in the perception of pain. Non-neuronal cells such as those of the immune system influence perception and modulation of pain by the nervous system. In post-dental surgery patients, the severity of the pain and the relief following administration of anti-inflammatory analgesics has been linked to the time course of inflammatory mediators. Similarly, the relief of post-operative pain after abdominal surgery is also associated with a reduction in expression of pro-inflammatory mediators. Administration of anti-cytokines to sciatica patients and subsequent pain relief further emphasizes the role of pro-inflammatory mediators in modulation of pain. Increased expression of inflammatory mediators may also alter response to analgesia. For example, rheumatoid patients with temporal mandibular joint disease with increased expression of interleukins prior to treatment demonstrate inadequate pain relief after administration of anti-TNF-. In addition, pain or its trauma impairs absorption of oral analgesics causing therapeutic failure. Improved analgesic pharmacotherapy may require a better understanding of the involvement of the inflammatory pathways.

A role for inflammatory mediators in the IL-18 mediated attenuation of LTP in the rat dentate gyrus

Pro-inflammatory cytokines are known to be elevated in several pathological conditions that are associated with deficits in cognition. We have previously demonstrated that interleukin-18 (IL-18) inhibits long-term potentiation (LTP) in the dentate gyrus in vitro. In this study we have examined the involvement of the inflammatory mediators COX-2 and iNOS in IL-18-mediated inhibition of LTP. The effect of an anti-inflammatory PPARγ agonist was also investigated. We report that the impairment of LTP by IL-18 is significantly attenuated by prior application of the COX-2 inhibitor, SC-236 and the iNOS inhibitor 1400W. These agents had no effect on paired pulse depression in the dentate gyrus. Furthermore, application of the PPARγ agonist ciglitazone also attenuated IL-18-mediated inhibition of LTP. We discuss a role for p38 MAP kinase in these effects. This study provides novel evidence for the involvement of inflammatory mediators in IL-18-mediated inhibition of LTP in the rat dentate gyrus in vitro.

Role of inflammatory mediators in the suppression of insulin receptor phosphorylation in circulating mononuclear cells of obese subjects

Obesity is associated with insulin resistance and inflammation. The circulating human mononuclear cell (MNC) has been shown to respond to low-dose insulin infusion. We have now investigated whether in obesity: (1) phosphorylated insulin receptor beta subunit (p-INSR-beta) is reduced in the MNC; (2) pro-inflammatory mediators including inhibitor of kappa light polypeptide gene enhancer in B cells-kinase beta (IKBKB), suppressor of cytokine signalling-3 (SOCS) and protein kinase C-beta 2 (PRKCB2) are increased and related to p-INSR-beta; and (3) the reduction in MNC p-INSR-beta is related to the reduction in insulin sensitivity. MNCs were prepared from fasting blood samples of 16 normal weight and 16 obese female subjects. Our data show that p-INSR-beta is reduced significantly in MNCs from obese subjects compared with that of normal controls. MNCs from obese subjects have higher IKBKB expression, increased nuclear factor kappa B (NFkappaB) binding and higher mRNA expression of TNFAIP1 and IL6 genes. NFkappaB binding, TNFAIP1 mRNA and plasma C-reactive protein are inversely related to p-INSR-beta. PRKCB2 mRNA and protein expression were significantly higher in the obese subjects and were related significantly to pro-inflammatory mediators but not to p-INSR-beta. SOCS3 mRNA expression was markedly elevated and positively related to pro-inflammatory mediators including IKBKB and PRKCB2 on the one hand and inversely related to p-INSR-beta on the other. We conclude that in obesity the MNC is characterised by reduced p-INSR-beta and increased inflammatory mediators including IKBKB, PRKCB2 and SOCS3. The increase in SOCS3 but not IKBKB or PRKCB2 is related inversely to p-INSR-beta and might mediate the inhibition of p-INSR-beta. These data elucidate the relationship between inflammation and insulin resistance using the MNC as a model.

Different inflammatory mediators induce inflammation and pain after application of liquid nitrogen to the skin

The application of liquid nitrogen to the skin induces inflammation and pain. However, there is little data on the role of inflammatory mediators in the production of these symptoms. We have developed an experimental model to study some aspects of the inflammatory response and its mediators following the application of cold. We have applied liquid nitrogen jets to subcutaneous air pouches in the dorsal skin of rats to study the kinetics of the migration of inflammatory cells; also to the ear for histopathological analysis and on the paws for edema and pain. Inflammatory mediators were identified by pharmacological means. The results showed that the cellular inflammatory response was characterized by persistent cell migration, mainly of granulocytes. Histopathology of the ears confirmed these findings. Histamine and sympathomimetic mediators were mainly responsible for the resultant swelling. However, the hypernociception that resulted involved other mediators including IL-1 and eicosanoids. These data suggest that interference with the release of inflammatory mediators might reduce the side effects of cryosurgery and prevent hyperalgesia and inflammation at the site of application of cold.

A Role for Inflammatory Mediators in the Induction of Immunoregulatory B Cells

UV exposure suppresses the immune response to a variety of microbial, fungal, and viral Ags. In addition, UV radiation is a complete carcinogen and the immune suppression induced by UV radiation is a major risk factor for skin cancer induction. In this study, we examined the mechanisms underlying the induction of immune suppression and tolerance induction by UV radiation. Transferring lymph nodes cells from UV-irradiated, FITC-sensitized mice into normal recipients transferred immune tolerance. Contrary to expectations, the cell responsible was an FITC(+), IL-10-secreting, CD19(+), B220(+) B cell. Because the lipid mediator of inflammation, platelet-activating factor (PAF) is released by UV-irradiated keratinocytes and is essential for the induction of immune suppression, we determined its role in tolerance induction. When UV-irradiated mice were injected with PCA 4248, a selective PAF receptor (PAFR) antagonist, transfer of tolerance was suppressed. However, immune suppression was not transferred when FITC(+) cells from the draining lymph nodes of UV-irradiated, PAFR-deficient donor mice were injected into the recipients. Because PCA 4248 also blocks serotonin receptor binding, we measured the effect that blocking both serotonin and PAFR binding has on the transfer of immune suppression. Only when both PAF and serotonin binding were blocked could we inhibit tolerance induction. These data identify a novel function for PAF and serotonin in modulating immune function, the activation of immunoregulatory B cells.

Haze after photorefractive keratectomy caused by iatrogenic lagophthalmos

A 22-year-old man had shortening of the levator muscle for a congenital blepharoptosis in the right eye in 2000. In September 2004, he was successfully treated by bilateral photorefractive keratectomy (PRK) for myopia and was asymptomatic with an uncorrected visual acuity of 20/20. In October 2005, right eye visual acuity decreased because of an inferiorly localized haze caused by nocturnal lagophthalmos. Fluorometholone eyedrops and lubrication induced full visual recovery after 2 months, but corresponding topographical abnormalities were only partially improved. Corneal exposure can induce haze after PRK, even in the long term. The efficacy of topical steroids indicates a role for inflammatory mediators in this condition. Eyelid position and dynamics must be evaluated before PRK to rule out lagophthalmos.

The Role of Inflammatory Mediators in the Synergistic Toxicity of Ozone and 1-Nitronaphthalene in Rat Airways

Ambient air is polluted with a mixture of pulmonary toxicants. Previous studies indicate that prior exposure to atmospheric oxidant pollutants such as ozone may significantly alter the response to other pollutants, such as 1-nitronaphthalene (1-NN). 1-NN, a component of the particulate exhaust from diesel engines, has been found at low concentrations in ambient air. Using a metabolomic approach, we investigated inflammatory responses in arachidonic and linoleic acid biochemical cascades (35 metabolites) and the expression of 19 cytokines/chemokines at three time points (2, 6, and 24 hr) following exposure to 1-NN with and without prior long-term O3 exposure. Long-term O3 exposure is associated with biochemical changes that have been shown to render the lung resistant to further O3 exposure. This study indicates that airways of O3-tolerant rats exhibited a low level of chronic inflammation, rendering the lungs more susceptible to other environmental pollutants such as 1-NN. Specifically, a 12.5-mg/kg dose of 1-NN to O3-tolerant rats produced significantly higher levels of cysteinyl-leukotrienes in bronchiolar lavage fluid even when compared to a 50-mg/kg dose of 1-NN in rats exposed to filtered air. Collectively, these results indicate that the combination of exposures as encountered in polluted ambient air are considerably more injurious to the lung than would be anticipated from previous studies employing single exposures. The observed synergism between O3 and 1-NN may be causally related to a shift in a T-helper 1 to T-helper 2 immune response in the airways.

Vascular Changes of the Retina and Choroid in Systemic Lupus Erythematosus: Pathology and Pathogenesis

Systemic lupus erythematosus (SLE) is a chronic autoimmune disorder that affects multiple organ systems. When eyes are involved, the principle manifestations are hemorrhage, retinal cotton wool spots, microangiopathy and vaso-occlusion. Research in the past two decades has significantly contributed to our understanding about this disease in general and its therapeutic management, although knowledge about the mechanism of ocular involvement and pathogenesis in SLE is limited. This is an important issue, because the ocular symptoms in this disease could be potentially sight threatening in acute cases. Here, we present an overview of the clinical and histopathologic features of retinal and choroidal vascular changes, as seen in patients with SLE. We discuss the role of immune complex deposition in vascular pathogenesis in the eye. Reports indicated an involvement of antiphospholipid antibodies (APAs) in the retinal and choroidal vasculopathy in SLE, although their precise role in this process is uncertain. It is important to look for mechanisms of immune complex-mediated vasculopathy and role of inflammatory mediators in this process in SLE. For this, established animal models can be utilized in research to learn about the precise role of various autoantibodies and complements involved in disease pathogenesis. A clear knowledge about the immunopathogenesis is warranted, and the rationale for the future therapy should be based on reducing vascular inflammation as well as ameliorating autoimmunity in this disease.

The intestinal injury after hemorrhagic shock and resuscitation exhibits inflammatory elements of reperfusion injury

Introduction: Intestinal injury after hemorrhagic shock is well recognized and thought to be a source of significant additional morbidity. A role for inflammatory mediators, particularly the complement system, in the genesis of either the local injury or its systemic consequences has been suspected. We hypothesize that reperfusion damage after hypotension and resuscitation is the cause of the intestinal injury, and that, as a result, the intestine would demonstrate the characteristic immunohistochemistry of reperfusion injury with deposition of IgM and complement. Methods: Male Sprague-Dawley rats were anesthetized and acutely bled to 50% of total blood volume for 90 minutes. The animals were then resuscitated with shed blood and monitored for survival for 72 hours. Small intestine from rats that did not survive the shock period, resuscitation, or 72 hours postoperative period was harvested and fixed in formalin. For comparison, small intestine from two sham rats and all shock animals that survived 72 hours was also harvested and fixed in formalin. Structural microscopic villous injury was assessed with a villous-injury scoring system by hemotoxylin and eosin staining. IgM and C3 deposition were assessed using immunohistochemistry. Results: Intestinal villous damage was demonstrated in all of the rats subjected to hemorrhagic shock and resuscitation as evidenced by hemotoxylin and eosin staining, but not in shams. Rats that died had higher intestinal injury scores than those that survived. Immunohistochemistry showed co-localization of IgM and C3 in those damaged intestinal villi that had not sloughed into the lumen. No microvillous damage, IgM, or C3 was demonstrated in the sham animals. Conclusions: These data demonstrate co-localization of IgM and C3 in the damaged rat intestinal villi of animals that underwent hemorrhagic shock and resuscitation, a characteristic feature of reperfusion injury in both the gut and hindlimb muscle. Treatment of the intestinal reperfusion injury occurring during shock and resuscitation could improve overall survival.

Plasticity of peripheral mechanisms of cough

The cough reflex pathway is characterized by a remarkable plasticity often resulting in a persistent and uncontrollable urge to cough during airway inflammation. In many instances cough becomes up regulated to the extent that ceases to fulfill its defensive role in protecting the airways. The exact mechanisms underlying this plasticity are unknown and likely involves a variety of factors influencing the function of the peripheral and central nervous system. This review outlines the evidence of increased cough sensitivity during airway disease. This is followed by a discussion of the peripheral mechanisms involved including the potential role of inflammatory mediators, neutrophins and changes in the airway mucosal structure. A greater understanding of the mechanisms leading to enhanced cough should lead to the development of more effective therapeutic strategies.

The Role of Inflammatory Mediators in Cartilage Degradation

Mounting evidence points to the importance of the role played by inflammatory mediators, such as cytokines or prostanoids, in the degradation of cartilage, not only in inflammatory arthritis, but also in degenerative joint diseases. In addition to well-known mediators such as interleukin-1, recent investigations have revealed the distinctive roles of a variety of other mediators in the regulation of cartilage matrix turnover. The present review focuses on the roles of inflammatory mediators in cartilage pathology that have been revealed by experimental evidence.

Role of Inflammatory Mediators in Angiogenesis

The angiogenic process involves several cell types and mediators, which interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. Angiogenesis occurs in several physiological and pathological conditions, such as embryo development and wound healing, diabetic retinopathy and tumours. Inflammatory cells, namely monocytes/macrophages, T lymphocytes and neutrophils, fully participate in the angiogenic process by secreting cytokines that may affect endothelial cell (EC) functions, including EC proliferation, migration and activation. Angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators. With regards to inflammatory cells and endothelium cross-talk, such balance is conceptually very similar to that of pro-inflammatory and anti-inflammatory mediators that modulate an appropriate inflammatory response. In this review we will mainly discuss the relevance of both physiological and pathological inflammatory processes in angiogenesis, with particular regards to microenvironmental contribution. We will also describe some of the most relevant pro-inflammatory cytokines in the modulation of the angiogenic process. Furthermore, we will concentrate on what has been recently reported about the mechanism by which some of these cytokines are induced during inflammation to promote a suitable microenvironment for angiogenesis and tumour progression. Pro-angiogenic cytokines, such as IL-1 and TNF, and anti-angiogenic cytokines such as IFN-gamma and IL-12, will be briefly described. We will try to provide a rationale for the use of both cytokines and cytokine blockades as novel potential pharmaceutical targets to modulate angiogenesis in chronic inflammation as well as in cancer.

Prevention of necrotising enterocolitis: Year 2004 and beyond

The incidence of necrotising enterocolitis (NEC) has not changed significantly despite the dramatic advances in perinatal–neonatal care. The absolute number of survivors of NEC is expected to rise, as prevention of prematurity, the single most important risk factor for the illness, continues to be difficult. Prevention of NEC has thus become an area of research priority. Given the role of inflammatory mediators in its pathogenesis newer immune modulators are being studied as potential agents for prevention/treatment of NEC. Caution, however, is warranted because the failure of sepsis trials in adults has clearly indicated that the concept of down-regulating the inflammatory response is deceptively simple. Clinical trials of any such promising preventative agent(s) need to be designed carefully and must include long-term neurodevelopmental outcomes as almost an entire population of high-risk preterm neonates will be exposed to their adverse effects. As new frontiers continue to be explored, the proven benefits of simple and safe interventions like antenatal glucocorticoid therapy and the preferential use of breast milk for feeding high-risk neonates must not be forgotten. Given that a single effective agent is unlikely in the near future, utilizing a package of “potentially better practices” seems to be the most appropriate strategy to prevent and minimize NEC.

Platelets at a crossroad of pathogenic pathways in sepsis

Platelets at a crossroad of pathogenic pathways in sepsis

Urotensin-II-mediated cardiomyocyte hypertrophy: effect of receptor antagonism and role of inflammatory mediators

Urotensin-II (U-II), the most potent mammalian vasoconstrictor identified, and its receptor, UT, exhibits increased expression in cardiac tissue and plasma in congestive heart failure (CHF) patients. Cardiomyocyte hypertrophy is primarily responsible for increased myocardial mass associated with cardiac injury. Neurohumoral factors such as angiotensin-II, endothelin-1, catecholamines, and inflammatory cytokines are thought to mediate this response. U-II shares similar biological activities with other hypertrophic G(q)-coupled receptor ligands such as angiotensin-II and endothelin-1, but a role for U-II in cardiomyocyte hypertrophy has not been characterized. The hypothesis of the current study was that U-II, acting through its G(q)-coupled receptor UT plays a hypertrophic role in cardiac hypertrophic remodeling. We report that adenoviral upregulation of the UT receptor "unmasked" U-II-induced hypertrophy in H9c2 cardiomyocytes, with a threshold response of 202+/-8 binding sites/cell. U-II was equally as efficacious as phenylephrine in inducing hypertrophy, measured by a reporter assay (EC(50) 0.7+/-0.2 nM) and [(3)H]-leucine incorporation (EC(50) 150+/-40 nM). A competitive peptidic UT receptor antagonist, BIM-23127, inhibited U-II-induced hypertrophy ( K(B) 34+/-6 nM). U-II did not affect cell proliferation or apoptosis, indicating that U-II is more hypertrophic than apoptotic or hyperplastic in cardiomyocytes. U-II (10 nM) stimulated interleukin-6 release in UT-expressing cardiomyocytes (4.6-fold at 6 h). Finally, in a rat heart failure model, cardiac ventricular mRNA expression of U-II, UT receptor, interleukin-6, and interleukin-1-beta is increased time-dependently following myocardial injury. These results indicate that U-II might play a role in cardiac remodeling associated with CHF by stimulation of cardiomyocyte hypertrophy via UT, and through upregulation of inflammatory cytokines. As such, UT antagonism may represent a novel therapeutic target for the clinical management of heart failure.

Role of inflammatory mediators in the function of intradental nerves

Role of inflammatory mediators in the function of intradental nerves