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PubMed1998

Systemic markers of inflammation in stable bronchiectasis.

Patients with bronchiectasis have an active local and systemic inflammatory response during infective exacerbations. Systemic markers of inflammation were investigated during a stable phase of their illness, because continued inflammation could affect their general health and be involved in disease progression. The relationship between levels of various systemic markers of inflammation and extent of disease on computed tomographic scan, lung function, sputum bacteriology and health related quality of life (HRQoL) was investigated in 87 noncystic fibrosis bronchiectasis patients. Several markers were elevated and correlated with the extent of disease and poor lung function. The total white cell count, neutrophil count and erythrocyte sedimentation rate correlated with both disease measures. Sputum bacteriology did not correlate with inflammation markers and patients with positive and negative cultures were similar. C-reactive protein and total white cell count correlated with some components of a disease-specific HRQoL questionnaire. In conclusion, patients with bronchiectasis in a stable phase have raised systemic markers of inflammation. Some markers, particularly the neutrophil count, correlate with disease severity. This result is in keeping with the hypothesis that the level of inflammation determines disease progression and health status.

Adult↗
PubMed2004

Inflammation and the degenerative diseases of aging.

Chronic inflammation is associated with a broad spectrum of neurodegenerative diseases of aging. Included are such disorders as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis, the Parkinson-dementia complex of Guam, all of the tauopathies, and age-related macular degeneration. Also included are such peripheral conditions as osteoarthritis, rheumatoid arthritis, atherosclerosis, and myocardial infarction. Inflammation is a two-edged sword. In acute situations, or at low levels, it deals with the abnormality and promotes healing. When chronically sustained at high levels, it can seriously damage viable host tissue. We describe this latter phenomenon as autotoxicity to distinguish it from autoimmunity. The latter involves a lymphocyte-directed attack against self proteins. Autotoxicity, on the other hand, is determined by the concentration and degree of activation of tissue-based monocytic phagocytes. Microglial cells are the brain representatives of the monocyte phagocytic system. Biochemically, the intensity of their activation is related to a spectrum of inflammatory mediators generated by a variety of local cells. The known spectrum includes, but is not limited to, prostaglandins, pentraxins, complement components, anaphylotoxins, cytokines, chemokines, proteases, protease inhibitors, adhesion molecules, and free radicals. This spectrum offers a huge variety of targets for new anti-inflammatory agents. It has been suggested, largely on the basis of transgenic mouse models, that stimulating inflammation rather than inhibiting it can be beneficial in such diseases as AD. If this were the case, administration of NSAIDs, or other anti-inflammatory drugs, would be expected to exacerbate conditions such as AD, PD, and atherosclerosis. However, epidemiological evidence overwhelmingly demonstrates that the reverse is true. This indicates that, at least in these diseases, the inflammation is harmful. So far, advantage has not been taken of opportunities indicated by these epidemiological studies to treat AD and PD with appropriate anti-inflammatory agents. Based on this evidence, classical NSAIDs are the most logical choice. Dosage, though, must be sufficient to combat the inflammation. Analysis of mRNA levels of inflammatory mediators indicates that the intensity of inflammation is considerably higher in AD hippocampus and in PD substantia nigra than in osteoarthritic joints. Thus, full therapeutic doses of NSAIDs, or combinations of anti-inflammatory agents, are needed to achieve the suggested neurological benefits.

Aging↗
PubMed2004

An inflammation score is better associated with basal than stimulated surrogate indexes of insulin resistance.

Most studies describe the association between one particular inflammatory marker and insulin resistance (IR), features of the metabolic syndrome, or progression to type 2 diabetes. We aimed to build an Inflammation Score as a tool to measure IR-associated inflammatory activity and to evaluate the ability of different surrogate indexes of IR to reflect the inflammatory state. We studied 81 subjects, aged 47.7 +/- 12 yr with a body mass index of 28.3 +/- 4 kg/m(2). The Inflammation Score was composed of: white blood cell count, erythrocyte sedimentation rate, C-reactive protein, and soluble fraction of TNF-alpha receptors 1 and 2. All the subjects underwent a frequently sampled iv glucose tolerance test, an oral glucose tolerance test, and surrogate indexes of IR were calculated. Each increase in the Inflammation Score was associated with a progressive increase in IR. We found significant differences across categories (0-1, 2, 3, and 4-5 points in the score) in age (P = 0.048), waist circumference (P = 0.015), body mass index (P = 0.013), blood pressure (P = 0.005), and uric acid (P = 0.031). The Inflammation Score was significantly associated with all but three of the surrogate IR indexes [2-h insulin glucose ratio, Gutt's insulin sensitivity (SI) index, and Avignon's 2-h SI index]. Surrogate indexes obtained from basal values showed a similar correlation with the Inflammation Score than the SI from frequently sampled iv glucose tolerance test. In summary, the Inflammation Score is a useful tool in the evaluation of IR-associated inflammatory activity. The surrogate indexes obtained using fasting glucose and insulin appear to better reflect this inflammatory state. Basal rather than stimulated indexes should be used in the evaluation of therapeutic measures aimed at modifying IR-associated inflammatory activity.

Adult↗
PubMed1992

Effects of L-156,602, a C5a receptor antagonist, on mouse experimental models of inflammation.

L-156,602, a C5a receptor antagonist, was found as an immunosuppressant with preferential effects on delayed-type hypersensitivity (DTH) in our screening program and it was shown that L-156,602 suppressed the efferent phase of DTH. Here, we tested its effects on experimental models of inflammation induced in mice. L-156,602 did not suppress serotonin- and carrageenan- induced inflammation while it completely suppressed concanavalin A-induced inflammation 4 h after elicitation. The inflammation appeared 24 h after the elicitation with concanavalin A and it was significantly suppressed by L-156,602. Muramyl dipeptide (MDP)-induced acute joint inflammation was also significantly suppressed by L-156,602. These results demonstrated the unique immunomodulating properties of L-156,602 in mouse experimental models of inflammation.

Animals↗
PubMed1995

Neurogenic switching: a hypothesis for a mechanism for shifting the site of inflammation in allergy and chemical sensitivity.

Neurogenic switching is proposed as a hypothesis for a mechanism by which a stimulus at one site can lead to inflammation at a distant site. Neurogenic inflammation occurs when substance P and other neuropeptides released from sensory neurons produce an inflammatory response, whereas immunogenic inflammation results from the binding of antigen to antibody or leukocyte receptors. There is a crossover mechanism between these two forms of inflammation. Neurogenic switching is proposed to result when a sensory impulse from a site of activation is rerouted via the central nervous system to a distant location to produce neurogenic inflammation at the second location. Neurogenic switching is a possible explanation for systemic anaphylaxis, in which inoculation of the skin or gut with antigen produces systemic symptoms involving the respiratory and circulatory systems, and an experimental model of anaphylaxis is consistent with this hypothesis. Food-allergy-iducing asthma, urticaria, arthritis, and fibromyalgia are other possible examples of neurogenic switching. Neurogenic switching provides a mechanism to explain how allergens, infectious agents, irritants, and possibly emotional stress can exacerbate conditions such as migraine, asthma, and arthritis. Because neurogenic inflammation is known to be triggered by chemical exposures, it may play a role in the sick building syndrome and the multiple chemical sensitivity syndrome. Thus neurogenic switching would explain how the respiratory irritants lead to symptoms at other sites in these disorders.

Environmental Exposure↗
PubMed1998

Nitric oxide and peroxynitrite production in ocular inflammation.

Recent studies have implicated nitric oxide and peroxynitrite in the pathogenesis of many diseases, such as septic shock, arthritis, lung disease, and atherosclerosis. Nitric oxide (.NO) exerts many diverse effects on vascular tone, affecting neurotransmission and cellular cytotoxicity/communication. Our laboratory and others have documented a proinflammatory role for .NO in ocular inflammation. Uveitis, which is an inflammation of the highly vascular uveal tract in the eye, is a debilitating condition that can lead to visual impairment and blindness. It is characterized by acute, recurrent, or persistent inflammation with disruption of the blood-aqueous barrier and is accompanied by protein leakage and leukocyte infiltration into the aqueous humor and anterior chamber. Systemic injection of endotoxin into mice and rats, or intraocular injection of endotoxin into mice, rats, and rabbits induces acute uveitis, which clinically and histologically resembles acute anterior uveitis in humans. These models facilitate the study of pathogenic mechanisms that contribute to ocular inflammation. In addition to .NO, superoxide anion radicals (O2.-), and peroxynitrite (ONOO-), the products of the reaction between .NO and O2.-, are also implicated in uveitis. The role of peroxynitrite in ocular inflammation is still largely unknown. Characterization of the roles of these important uveitic mediators in the ocular inflammatory response will provide information critical to the understanding of the pathogenesis of intraocular inflammation so that more effective therapeutic intervention(s) can be developed.

Animals↗
PubMed2005

Relationships among bacteria, upper airway, lower airway, and systemic inflammation in COPD.

STUDY OBJECTIVE: The upper and lower airways are continuous. While upper airway symptoms are common in COPD patients, with accumulating evidence to suggest increased nasal inflammation, the relationships among upper airway, lower airway, and systemic inflammatory indexes have not been studied. We aimed to confirm that there is heightened nasal inflammation in COPD patients, to test the hypothesis that the degree of upper airway inflammation relates to the degree of lower airway inflammation, and to investigate the underlying associations with bacterial carriage and the systemic inflammatory response. DESIGN: Prospective cohort study. SETTING: Outpatient Department, London Chest Hospital, London, UK. PARTICIPANTS: Forty-seven patients with COPD and 12 control subjects of similar age, sex, and smoking status. MEASUREMENTS: Serum, nasal wash fluid, and sputum samples were obtained from 47 stable patients with COPD for the analysis of inflammatory indexes and bacterial colonization. Nasal wash fluid specimens were obtained from 12 control subjects. RESULTS: COPD patients had an increased nasal interleukin (IL)-8 concentration compared to control subjects (difference, 97.2 pg/mL; p = 0.009). The nasal IL-8 concentration in COPD patients correlated with that in sputum (r = 0.30; p = 0.039). In both the upper and lower airways of patients with COPD, the IL-8 concentration was associated with indexes of bacterial colonization. Patients colonized with a sputum potentially pathogenic microorganism had a higher total nasal bacterial load (difference, 1.5 log cfu/mL; p = 0.016). We did not find significant relationships between the degree of upper or lower airway inflammation, or bacterial carriage, and the systemic inflammatory response. CONCLUSIONS: COPD is associated with an increased nasal concentration of the neutrophil chemoattractant protein IL-8, the degree of which reflects that present in the lower airway. A relationship between lower airway bacterial colonization, postnasal drip, and higher nasal bacterial load may suggest a mechanism underlying this finding. This study is the first to report a correlation between the degree of upper and lower airway inflammation in COPD.

Aged↗
PubMed2003

Semen polymorphonuclear neutrophil leukocyte elastase as a diagnostic and prognostic marker of genital tract inflammation--a review.

Elastase is a protease released by polymorphonuclear neutrophils (PMN) during the inflammatory process. Since 1987, seminal elastase-inhibitor complex (Ela/alpha1-PI) has been proposed as a marker of male silent genital tract inflammation. Measured by immunoassay in seminal plasma, Ela/alpha1-PI at a cut-off level of > or = 230 microg/l, is useful in the detection of genital tract inflammation. The prevalence of increased seminal Ela/alpha1-PI in infertile men is significantly higher than that observed in fertile men. The Ela/alpha1-PI level is positively correlated with other seminal fluid markers of male genital tract inflammation: reduced semen volume, citric acid, fructose, and increased albumin, complement component C3, caeruloplasmin, immunoglobulins IgG and IgA, and cytokines interleukins-8 and -6. A higher seminal Ela/alpha1-PI level is significantly associated with tubal damage in female partners. After antibiotic therapy, a decrease of Ela/alpha1-PI level is observed. The presence of tubal damage in the partner may negatively affect the response to antibiotic treatment. A higher seminal Ela/alpha1-PI is associated with lower percentage of sperm with single-stranded deoxyribonucleic acid (DNA) and better fertilization rate in in vitro fertilization. Besides infertility, the determination of Ela/alpha1-PI is useful to confirm the presence of prostate and other male accessory gland bacterial inflammation. Screening for PMN Ela/alpha1-PI is easy to perform and reproducible and is a reliable quantitative test for diagnosis and prognosis of silent genital tract inflammation of couples. Moreover, sequential determinations allow the follow-up of inflammation during and after therapy.

Biomarkers↗
PubMed2006

Relationship between serum sialic acids, sialic acid-rich inflammation-sensitive proteins and cell damage in patients with acute myocardial infarction.

The role of sialic acid (SA) in the pathogenesis of atherosclerosis and as a predictor of cardiovascular events has attracted much attention in recent years. However, most studies investigating the role of total and lipid-bound sialic acids (TSA and LSA) in the pathogenesis of atherosclerosis lack information on the reason for the elevated SA concentrations in coronary heart disease and myocardial infarction. Since the inflammation-sensitive proteins are glycoproteins with SA residues, an increase in their levels due to some type of acute-phase reaction or inflammation could be responsible for the elevated TSA levels in acute myocardial infarction (AMI). Elevated serum SA levels might also be due to either shedding or secretion of free SA from the cell or cell membrane surface if neuraminidase levels are increased, or to the release of cellular SA-containing glycolipids and/or glycoproteins into plasma from myocardial cells after AMI. The aim of the present study was to investigate both the possible role of SA-rich inflammation-sensitive proteins and the cell damage due to elevated serum TSA levels in AMI. A possible role of serum LSA as an indicator of the shedding or secretion of SA from the cell or cell membrane surface in AMI was also evaluated. The study included 38 subjects with AMI and 32 healthy volunteers. Serum TSA and LSA were determined using the methods of Warren and Katopodis, respectively. The concentrations of serum SA-rich inflammation-sensitive proteins, namely alpha1-antitrypsin, alpha2-macroglobulin and ceruloplasmin were determined immunoturbidimetrically. Our data showed that: a) mean levels of serum TSA and LSA and SA-rich inflammation-sensitive proteins in patients with AMI were significantly increased; and b) there was a significant positive correlation between TSA and LSA and alpha1-antitrypsin in patients with AMI. Since the transfer of free SA to lipoproteins is required for an increase in serum LSA levels, and free SA for this transfer can be provided by the secretion of SA from the cell, it is obvious that the shedding or secretion of SA from the cell membrane surface or release of cellular SA from cells into the bloodstream due to cell damage after AMI also occur after AMI. As a result, we can report that either the shedding or secretion of SA from the cell or cell membrane surface and the increased output of SA-rich inflammation-sensitive proteins may together be responsible for the elevated TSA levels in AMI.

Biomarkers↗
PubMed2003

6th World Congress on Inflammation.

The 6th World Congress on Inflammation was held in the Vancouver Convention and Exhibition Center. This biennial meeting was organised by the Inflammation Research Association (USA) and Triangle 3 Ltd (UK), under the auspices of the International Association of Inflammation Societies. This meeting aimed to promote international cooperation amongst inflammation scientists and provide a communication network for various inflammation societies from around the world. The conference covered the most up-to-date concepts in inflammation, new drugs and treatments, and advances in cell biology. However, there were some topics which were either novel to many attendees or which provided links to a number of presentations, thus underlining their importance. The following is by no means an exhaustive review, but merely reflects the authors' interests.

Animals↗
PubMed2005

Activin induces tactile allodynia and increases calcitonin gene-related peptide after peripheral inflammation.

Calcitonin gene-related peptide (CGRP) is a sensory neuropeptide important in inflammatory pain that conveys pain information centrally and dilates blood vessels peripherally. Previous studies indicate that activin A increases CGRP-immunoreactive (IR) sensory neurons in vitro, and following wound, activin A protein increases in the skin and more neurons have detectable CGRP expression in the innervating dorsal root ganglion (DRG). These data suggest some adult sensory neurons respond to activin A or other target-derived factors with increased neuropeptide expression. This study was undertaken to test whether activin contributes to inflammatory pain and increased CGRP and to learn which neurons retained plasticity. After adjuvant-induced inflammation, activin mRNA, but not NGF or glial cell line-derived neurotrophic factor, increased in the skin. To examine which DRG neurons increased CGRP immunoreactivity, retrograde tracer-labeled cutaneous neurons were characterized after inflammation. The proportion and size of tracer-labeled DRG neurons with detectable CGRP increased after inflammation. One-third of CGRP-IR neurons that appear after inflammation also had isolectin B4 binding, suggesting that some mechanoreceptors became CGRP-IR. In contrast, the increased proportion of CGRP-IR neurons did not appear to come from RT97-IR neurons. To learn whether central projections were altered after inflammation, CGRP immunoreactivity in the protein kinase Cgamma-IR lamina IIi was quantified and found to increase. Injection of activin A protein alone caused robust tactile allodynia and increased CGRP in the DRG. Together, these data support the hypothesis that inflammation and skin changes involving activin A cause some sensory neurons to increase CGRP expression and pain responses.

Activins↗
PubMed2004

The relationship between inflammation and the anticoagulant pathway: the emerging role of endothelial nitric oxide synthase (eNOS).

Inflammation represents the interaction of the immune and coagulation systems in an attempt to restore normal hemostasis following injury. The underlying basis of the interrelationship between these two physiological systems revolves around the following: a) the activation of coagulation by inflammation, b) the augmentation of the inflammatory response by coagulation, c) the significant attenuation of inflammation by the anticoagulant response and d) the separate influence of the vascular endothelium on coagulation and inflammation as well as its mediation or control of the cross-talk between these two physiological systems. In hemostasis, the protein C anticoagulant pathway is a major mechanism that functions to prevent the development of a pathological thrombus through the regulation of the procoagulant pathway. The endothelium is essential in maintaining a physiological balance between the anticoagulant and procoagulant pathways with proinflammatory cytokines functioning, in part, to regulate endothelial-cell- surface associated coagulation and anticoagulation proteins. In addition to its anticoagulant properties, activated protein C can also function as a regulator of proinflammatory cytokine production. Current evidence suggests that activated protein C may act to control inflammation through NF-kappaB and/or nitric oxide synthase. A better understanding of the relationship between APC and inflammation may provide new targets for drug design.

Blood Coagulation↗
PubMed1997

Cytokines in acute and chronic inflammation.

Inflammation is mediated by a variety of soluble factors, including a group of secreted polypeptides known as cytokines. Inflammatory cytokines can be divided into two groups: those involved in acute inflammation and those responsible for chronic inflammation. This review describes the role played in acute inflammation by IL-1, TNF-alpha, IL-6, IL-11, IL-8 and other chemokines, G-CSF, and GM-CSF. It also describes the involvement of cytokines in chronic inflammation. This latter group can be subdivided into cytokines mediating humoral responses such as IL-4, IL-5, IL-6, IL-7, and IL-13, and those mediating cellular responses such as IL-1, IL-2, IL-3, IL-4, IL-7, IL-9, IL-10, IL-12, interferons, transforming growth factor-beta, and tumor necrosis factor alpha and beta. Some cytokines, such as IL-1, significantly contribute to both acute and chronic inflammation. This review also summarizes features of the cell-surface receptors that mediate the inflammatory effects of the described cytokines.

Acute Disease↗
PubMed2003

Proteinase-activated receptor-2-induced colonic inflammation in mice: possible involvement of afferent neurons, nitric oxide, and paracellular permeability.

Activation of colonic proteinase-activated receptor-2 (PAR-2) provokes colonic inflammation and increases mucosal permeability in mice. The mechanism of inflammation is under debate and could be neurogenic and/or the consequence of tight-junction opening with passage of exogenous pathogens into the lamina propria. The present study aimed to further characterize the inflammatory effect of PAR-2 activation by investigating: 1) the role of NO, 2) the role of afferent neurons, and 3) a possible cause and effect relationship between colonic paracellular permeability changes and mucosal inflammation. Thus, intracolonic infusion to mice of the PAR-2-activating peptide, SLIGRL, increased both myeloperoxidase (MPO) activity and damage scores indicating colonic inflammation, and enhanced colonic permeability to (51)Cr-EDTA from 2 to 4 h after its infusion. NO synthase inhibitors, L-NAME and aminoguanidine, as well as the neurotoxin capsaicin and NK1, calcitonin gene-related peptide (CGRP) receptor antagonists, SR140333 and CGRP(8-37), prevented SLIGRL-induced MPO and damage score increases and permeability. In contrast, although the tight-junction blocker, 2,4,6-triaminopyrimidine, and the myosin L chain kinase inhibitor, ML-7, prevented SLIGRL-induced increase in permeability, they did not prevent MPO and damage score increases. Taken together our data show that both NO and capsaicin-sensitive afferent neurons are involved in PAR-2-mediated colonic inflammation and paracellular permeability increase. Nevertheless, the inflammation process is not a consequence of increased permeability which results at least in part from the activation of myosin L chain kinase.

Administration, Rectal↗
PubMed2005

IL-12 induction of mRNA encoding substance P in murine macrophages from the spleen and sites of inflammation.

Substance P (SP), a neuropeptide, interacts with the neurokinin 1 receptor (NK-1R) on immune cells to help control IFN-gamma production. In murine schistosomiasis mansoni, schistosome worms produce ova that incite focal Th2-type granulomatous inflammation within the liver and intestines. Normal gut is characterized by a controlled state of inflammation. IL-10 knockout mice develop chronic Th1-type colitis spontaneously. Both schistosome granulomas and gut mucosa display an SP immune regulatory circuit. However, the origin and regulation of SP production at these sites of inflammation are poorly understood. Macrophages are a potential source of SP. We therefore studied macrophages (F4/80(+)) from these models of inflammation. SP mRNA (preprotachykinin A (PPT A)) was detected within the schistosome granuloma, spleen, and lamina propria macrophages. Compared with those from wild-type mice, granuloma macrophages from STAT6(-/-) mice had 10-fold higher PPT A mRNA expression, whereas in STAT4(-/-) animals, PPT A mRNA expression was nearly abolished. IL-12 signals via STAT4 to induce Th1-type inflammation. It was demonstrated that IL-12, but not IL-18, induces SP mRNA expression in resting splenic macrophages from Schistosoma-infected mice and in wild-type lamina propria mononuclear cells. Thus, macrophages are a source for SP at these sites of chronic inflammation, and IL-12 and STAT4 are regulators of macrophage SP mRNA expression.

Animals↗
PubMed2005

Mucosal B cell deficiency in IgA-/- mice abrogates the development of allergic lung inflammation.

We have investigated the consequence of lack of IgA on host immunity using a murine model of allergic lung inflammation. Mice with a targeted disruption of the alpha-switch region and 5' H chain gene (IgA(-/-) mice), which lack total IgA, developed significantly reduced pulmonary inflammation with fewer inflammatory cells in lung tissue and bronchoalveolar lavage fluids, as well as reduced levels of total and IgG1 OVA-specific Abs and decreased IL-4 and IL-5 in bronchoalveolar lavage fluids compared with IgA(+/+) controls, following allergen sensitization and challenge. This defect was attributable to fewer B cells in the lungs of IgA(-/-) mice. Polymeric IgR-deficient (pIgR(-/-)) mice, which lack the receptor that transports polymeric IgA across the mucosal epithelium where it is cleaved to form secretory IgA, were used to assess the contribution of secretory IgA vs total IgA in the induction of allergic lung inflammation. pIgR(-/-) and pIgR(+/+) mice had comparable levels of inflammation, demonstrating that IgA bound to secretory component is not necessary for the development of allergic lung inflammation, although this does not necessarily rule out a role for transudated IgA in lung secretions because of "mucosal leakiness" in these mice. The results indicate that Ag-specific B cells are required at mucosal surfaces for induction of inflammation and likely function as major APCs in the lung for soluble protein Ags.

Administration, Intranasal↗
PubMed1999

Inflammation, sepsis, and coagulation.

The molecular links between inflammation and coagulation are unquestioned. Inflammation promotes coagulation by leading to intravascular tissue factor expression, eliciting the expression of leukocyte adhesion molecules on the intravascular cell surfaces, and down regulating the fibrinolytic and protein C anticoagulant pathways. Thrombin, in turn, can promote inflammatory responses. This creates a cycle that logically progresses to vascular injury as occurs in septic shock. Most complex systems are regulated by product inhibition. This inflammation-coagulation cycle seems to follow this same principle with the protein C pathway serving as the regulatory mechanism. The molecular basis by which the protein C pathway functions as an anticoagulant is relatively well established compared to the mechanisms involved in regulating inflammation. As one approach to identifying the mechanisms involved in regulating inflammation, we set out to identify novel receptors that could modulate the specificity of APC in a manner analogous to the mechanisms by which thrombomodulin modulates thrombin specificity. This approach led to the identification of an endothelial cell protein C receptor (EPCR). To understand the mechanism, we obtained a crystal structure of APC (lacking the Gla domain). The crystal structure reveals a deep groove in a location analogous to anion binding exosite 1 of thrombin, the location of interaction for thrombomodulin, platelet thrombin receptor and fibrinogen. Thrombomodulin blocks the activation of platelets and fibrinogen without blocking reactivity with chromogenic substrates or inhibitors. Similarly, in solution, EPCR blocks factor Va inactivation without modulating reactivity with protease inhibitors. Thus, these endothelial cell receptors for the protein C system share many properties in common including the ability to be modulated by inflammatory cytokines. Current studies seek to identify the substrate for the APC-EPCR complex as the next step in elucidating the mechanisms by which the protein C pathway modulates the response to injury and inflammation.

Amino Acid Chloromethyl Ketones↗
PubMed1999

Does androgen insufficiency cause lacrimal gland inflammation and aqueous tear deficiency?

PURPOSE: The current investigators have shown that androgen treatment suppresses inflammation and stimulates the function of lacrimal glands in mouse models of Sjögren's syndrome. Recently, others have hypothesized that androgen insufficiency induces an autoimmune process in lacrimal tissue, leading to inflammation, a Sjögren's syndrome-like pathology, and aqueous tear deficiency. The purpose of the present study was to test this hypothesis. METHODS: Lacrimal glands were obtained from adult testicular feminized (Tfm) and control mice; castrated rats, guinea pigs, and rabbits; and castrated rats without anterior or whole pituitary glands and were processed for histology and image analysis. Tear volumes were measured in mice, in patients taking antiandrogen medications, and in age-matched human control subjects. RESULTS: Tfm mice, which are completely resistant to classical androgen action, did not have increased lymphocyte infiltration in their lacrimal glands or decreased tear volumes. No inflammation was evident in lacrimal tissues of male or female rats, guinea pigs, or rabbits 12 to 31 days after castration, no inflammation existed in rat lacrimal glands 15 to 31 days after orchiectomy and pituitary removal, and no aqueous tear deficiency was apparent in patients receiving antiandrogen therapy. CONCLUSIONS: Androgen deficiency may promote the progression of Sjögren's syndrome and its associated lacrimal gland inflammation, meibomian gland dysfunction, and severe dry eye. However, androgen insufficiency alone does not cause lacrimal gland inflammation, a Sjögren's syndrome-like pathology in lacrimal tissue, or aqueous tear deficiency in nonautoimmune animals and humans.

Aged↗