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Hemostatic serine proteinases-thrombin, Factor VIIa, Factor Xa, play the central role in blood coagulation and thrombosis. Activation of coagulation and generation of active proteinases is initiated by tissue factor (TF) that is expressed by cells of the innate immune system and endothelial cells after tissue damage and cell activation induced by trauma, infection, hypoxia and other cell injury. Coagulation and inflammation are the essential part of the defensive host response. These processes have several connecting points account for the associate and/or the interaction between coagulation and inflammation pathways. The first link between these processes is endothelium, which after damage expresses the adhesive proteins (vWF,P-selectin), inductors and receptors, involved in both coagulation and inflammation. The second link is platelets, which stored in and after activation release proteins with procoagulant and proinflammatory properties. The third link is the serine proteinases, which produced for blood coagulation and activate via its specifical receptors--PARs (proteinase activated receptors) the cells of both coagulation and inflammation system thereby controlling these processes. The generation of these proteinases is initiated by tissue factor (TF) which triggers blood coagulation at sites of tissue injury by selective binding of FVIIa. TF/VIIa complexes with substrate--FX that is activated to FXa. TF/VIIa/Xa can activate both the inflammatory responses of endothelial and other cells and also blood coagulation through stimulation of thrombin generation. This review summarizes the latest data on the blood coagulation activation that include generation of active surface for coagulation, generation of hemostatic serine proteinases and its role as signalling molecules that via PARs and other receptors involved in regulation and control of the interaction of blood coagulation and inflammation and illustrates the potential for therapeutic intervention.
The ETS-domain transcription factor family can be divided into a series of subfamilies. Elk-1 represents the founding member of the ternary complex factor (TCF) subfamily. By focusing on the TCF subfamily, we can demonstrate the complexities that exist in the function and regulation of ETS-domain transcription factors. This article focuses on Elk-1 in detail and summarizes the functions of other TCFs. The key themes covered include the domain structure of the TCFs, the mechanisms of complex formation with serum response factor, regulation of TCFs by mitogen-activated protein kinase cascades, and transcriptional regulatory properties of the TCFs. Finally, the emerging role of the TCFs in vivo is discussed. A picture is developing indicating that, while these proteins exhibit significant sequence and functional conservation, key differences in their structure and regulation are being identified which may relate to unique functions of these proteins in vivo.
Histological data show perivascular recruitment of inflammatory cells in lung inflammation. However, the process of perivascular inflammation is yet-to-be characterized in any systematic manner at cell and molecular levels. Therefore, we investigated impact of genetic background on perivascular inflammation in acute or chronic airway inflammation in different strains of mice. Further, to address molecular mechanisms of perivascular inflammation, we examined immunohistochemical expression of vascular adhesion protein-1 (VAP-1) in chronic airway inflammation. Histological scoring revealed time and strain specific differences in perivascular recruitment of inflammatory cells in chronic and acute airway inflammation (P < 0.05). The data show that A/J strain is significantly more susceptible for perivascular inflammation followed by BALB/c and C57BL/6, while C3H/HeJ strain showed no perivascular accumulation of inflammatory cells. Of the two strains examined for perivascular inflammation in acute airway inflammation, BALB/c showed more accumulation of inflammatory cells compared to C57BL/c. VAP-1 expression occurred in the endothelium of pulmonary arteries but not in alveolar septa or airways in the control as well as challenged mice. In the inflamed lungs from A/J mice, the VAP-1 staining in pulmonary arteries was more intense compared to the other strains. VAP-1 staining was generally observed throughout the pulmonary arterial wall in chronic lung inflammation. These data show that periarterial inflammation is influenced by the genetic background, and may be partially regulated by VAP-1.
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The neuropeptide alpha-melanocyte-stimulating hormone (alpha-MSH) has potent antipyretic and antiinflammatory properties. When administered systemically, the naturally occurring molecule and its COOH-terminal tripeptide sequence inhibit inflammation induced by peripherally applied irritants and intradermal injections of mediators of inflammation such as interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF alpha). We recently found that alpha-MSH can act solely within the brain to inhibit inflammation caused by a general irritant applied to the skin. This activity appears to be shared with salicylate drugs and the combined observations suggest the existence of descending neurogenic antiinflammatory signals capable of modulating inflammation in peripheral tissues. To improve our knowledge of the scope of this action of the peptide, alpha-MSH was injected into the cerebral ventricles (i.c.v.) of mice that had received intradermal injections in the ear of mediators of inflammation: IL-1 beta, IL-8, leukotriene B4, and platelet-activating factor. The centrally administered peptide inhibited the actions of all of these proinflammatory agents as determined from comparisons with measures of ear edema over time in control animals; this indicates that the central peptide can alter inflammation induced in the periphery by major mediators of inflammation. In tests confined to IL-1 beta, central administration of alpha-MSH(11-13) was also effective. These findings support the concept of a descending neurogenic antiinflammatory influence promoted by an action of alpha-MSH within the brain, an inhibitory influence that is not restricted to modulation of just one or a limited set of the mediators of inflammation.
John Hunter's A Treatise on the Blood, Inflammation and Gunshot Wounds was published in 1794. Throughout the nineteenth century this was considered the most important study of inflammation and has been widely quoted since. After a section on the nature of blood and the circulatory system, in which he describes the vascular supply in detail, he passes on to an extensive survey of inflammation. This is based mainly on his wide clinical experience, including that as a military surgeon. He, however, supplements this with a number of experiments, some of which are classic. He bases his observations on the four cardinal signs of Celsus (redness, heat, swelling and pain). Inflammation is then divided into three main groups: adhesive, suppurative and ulcerative. He discusses the nature of pus and the formation and treatment of abscesses. He describes his experiments on the transplantation of tissues under the general heading of adhesive inflammation. This, he states, underlies the union of wounds and thus the union of tissues after transplantation. Although unaware of the role of infecting organisms as a cause of inflammation, he makes observations on inflammation in smallpox, venereal infections and tuberculosis. He relates these to his observations on inflammatory aspects of wound healing. Lister was particularly influenced by Hunter's observations in the development of antisepsis. As well as the local effect of inflammation, Hunter was concerned with the constitutional effects such as fever.
OBJECTIVES: The study clarified whether the T-helper (Th)1/Th2 imbalance existed only in coronary arterial inflammation or in both coronary arterial inflammation and myocardial inflammation and explored the significance of the imbalance of Th1/Th2 function after acute myocardial infarction (AMI). BACKGROUND: There are two different inflammatory processes in patients with AMI: the coronary arterial inflammation that leads to the pathogenesis of AMI and the myocardial inflammation after AMI that leads to ventricular remodeling, which are positively and negatively regulated by Th1 and Th2 lymphocytes, respectively. METHODS: Peripheral blood mononuclear cells from 33 AMI patients, 22 unstable angina (UA) patients and splenocytes from 35 AMI Wistar rats were collected. Cytokine-producing Th cells were ambulatorily monitored by 3-color flow cytometry. Interferon (IFN)-gamma and interleukin (IL)-4 mRNA in the rat myocardium and chemokine receptors CCR3,CCR5 and CXCR3 mRNA on the surface of rat T-lymphocytes after AMI were measured by RT-PCR. RESULTS: IFN-gamma-producing T-cells significantly increased in patients with AMI and UA within 24 hours after the onset of symptom. The high ratio of IFN-gamma-producing T-cells recovered 1 week after the onset in UA patients, while it could be examined 1 week and even 1 month after the onset in AMI patients. The up-regulation of Th1 cell function is consistent with bad heart function. There was no significant difference on the frequencies of IL-4-producing T-cells between each group. 1 week, 2 weeks and 1 month after AMI, IFN-gamma mRNA increased in the myocardium of rats, but there was no significant change on global Th cell functions. CONCLUSIONS: Th1/Th2 functional imbalance exists in both coronary arterial inflammation and myocardial inflammation processes. The up-regulation of Th1 cell-functions may participate in the immune-mediated ventricular remodeling after AMI.
Flavonoids from plant origin show anti-inflammatory activity in vitro and in vivo. In addition to inhibition of inflammation-associated enzymes, such as cyclooxygenases (COX) and lipoxygenases, they have been found to regulate the expression of inflammation-associated proteins from in vitro experiments. In order to prove in vivo behavior and the potential for beneficial use against inflammatory skin disorders, the effect of wogonin (5,7-dihydroxy-8-methoxyflavone) on in vivo expression of several inflammation-associated genes was examined in the intact as well as in the inflamed mouse skin by reverse transcriptase-polymerase chain reaction analysis. When applied topically on the intact skin, only a high dose treatment of wogonin (1000 microg/ear/3 days) slightly increased COX-1 and fibronectin mRNA. On the other hand, wogonin at the doses of 250-1000 microg/ear/3 days potently lowered mRNA levels of COX-2 and tumor necrosis factor-alpha with less effect on intercellular adhesion molecule-1 and interleukin-1beta in a sub-chronic skin inflammation model of tetradecanoylphorbol-13-acetate-induced ear edema (multiple treatment). The decrease of prostaglandin E(2) concentration (27.3-34.3%) was concomitantly observed in the wogonin-treated groups. A similar effect was also observed in an acute inflammation model of arachidonic acid-induced ear edema. From the present study, wogonin was proved to differentially regulate the expression of inflammation-associated genes in vivo and to become a useful therapeutic agent for skin inflammatory diseases mainly due to its modulation of the expression of proinflammatory molecules.
The Working Group on Neurogenic Inflammation proposed 11 testable hypotheses in the three domains of neurogenic inflammation, perceptual and central integration, and nonneurogenic inflammation. The working group selected the term people reporting chemical sensitivity (PRCS) to identify the primary subject group. In the domain of neurogenic inflammation, testable hypotheses included: PRCS have an increased density of c-fiber neurons in symptomatic tissues; PRCS produce greater quantities of neuropeptides and prostanoids than nonsensitive subjects in response to exposure to low-level capsaicin or irritant chemicals; PRCS have an increased and prolonged response to exogenously administered c-fiber activators such as capsaicin; PRCS demonstrate augmentation of central autonomic reflexes following exposure to agents that produce c-fiber stimulation; PRCS have decreased quantities of neutral endopeptidase in their mucosa; exogenous neuropeptide challenge reproduces symptoms of PRCS. In the domain of perceptual and central integration, testable hypotheses included: PRCS have alterations in adaptation, habituation, cortical representation, perception, cognition, and hedonics compared to controls; the qualitative and quantitative interactions between trigeminal and olfactory systems are altered in PRCS; higher integration of sensory inputs is altered in PRCS. In the domain of nonneurogenic inflammation, testable hypotheses included: increased inflammation is present in PRCS in symptomatic tissues and is associated with a heightened neurosensory response; PRCS show an augmented inflammatory response to chemical exposure. The working group recommended that studies be initiated in these areas.
Pulmonary exposure to diesel exhaust particles (DEP) enhances lung inflammation related to bacterial endotoxin (lipopolysaccharide [LPS]) in mice. Severe lung inflammation can reportedly induce coagulatory abnormalities and systemic inflammation. This study examined the effects of components of DEP on lung inflammation, pulmonary permeability, coagulatory changes, systemic inflammatory response, and lung-to-systemic translocation of LPS in a murine model of lung inflammation. ICR mice were divided into six experimental groups that intratracheally received vehicle, LPS (2.5 mg/kg), organic chemicals in DEP (DEP-OC; 4 mg/kg) extracted with dicloromethane), residual carbonaceous nuclei of DEP (washed DEP: 4 mg/kg), DEP-OC + LPS, or washed DEP + LPS. Both DEP components exacerbated lung inflammation, vascular permeability, and the increased fibrinogen and E-selectin levels induced by LPS. With overall trends, the exacerbation was more prominent with washed DEP than with DEP-OC. Washed DEP + LPS significantly decreased activated protein C and antithrombin-III and elevated circulatory levels of interleukin (IL)-6, keratinocyte chemoattractant (KC), and LPS as compared with LPS alone, whereas DEP-OC + LPS elevated IL-6, KC, and LPS without significance. These results show that DEP components, especially washed DEP, amplify the effects if LPS on the respiratory system and suggest that they contribute to the adverse health effects of particulate air pollution on the sensitive populations with predisposing vascular and/or pulmonary diseases, including ischemic vascular diseases and respiratory infection.
Direct evidence that inflammation is linked to carcinogenesis has yet to be established. Very few data are available on the developmental phases of inflammation-induced immune dysfunction that may lead to tumorigenesis. In a series of studies conducted in the 1980s and 1990s, an experimental model of acute and chronic inflammation was established in guinea pig conjunctiva by topical application of fluoresceinyl ovalbumin (FLOA) for up to 30 months. In this updated report, some of the findings are reanalyzed and expanded to identify that at lease 3 developmental phases were involved during the entire course of inflammatory responses including (1) an acute response (phase A) involving IgE-mast cell sensitization and degranulation; (2) an intermediate phase (phase B), a desensitization phenomenon and loss of mast cell function and neovascularization; (3) a chronic response (phase C) and induction of massive lymphoid hyperplasia, follicular formation with germinal centers, increased swollen goblet cells, extensive epithelial thickening and thinning, and angiogenesis. The results suggest evidence of a direct association between inflammation and the development of tumor-like lesions in lymphoid tissues and extensive changes in adjacent epithelia. Confirmation that inflammation induces irreversible changes in lymphoid and epithelial tissues leading to lymphoid tumorigenesis and/or carcinogenesis requires further studies. Understanding the developmental phases of immune dysfunction may provide unique opportunities for diagnosis and treatment of inflammatory diseases, autoimmune disorders, and cancers including lymphomas associated with Sjogren syndrome, squamous cell carcinoma of the conjunctiva, and other lymphomas or epithelial cancers. It is suggested that inflammatory mediators are ideal targets (biomarkers) for diagnosis, chemoprevention, and therapy for several cancers.
Excessive local production of nitric oxide (NO) has been suggested to play a role in rodent models of airway inflammation and in pulmonary diseases such as asthma. However, even given the plethora of data available including gene expression data, pharmacological data, and gene deletion studies in animal models, it is still not clear which nitric-oxide synthase (NOS) isoform is involved in eosinophilic airway inflammation. In this rat study, the nonselective NOS inhibitor L-NAME (N(G)-nitro-L-arginine methyl ester), but not a selective inducible NOS (iNOS) inhibitor 1400W (N-3-(aminomethyl)benzyl)acetamidine), impacted on Sephadex-induced inflammation by significantly inhibiting lung edema, eosinophil infiltration, tumor necrosis factor alpha, interleukin-13, and eotaxin levels in the lung tissue. Furthermore, iNOS gene expression was not induced following Sephadex administration, which confirms that iNOS does not play a role in this model. To demonstrate that this phenomenon was not restricted to this model of asthma, L-NAME, but not 1400W, was shown to reduce eosinophilia in an antigen-induced model. However, in contrast to the Sephadex model, there was an induction of iNOS gene expression after antigen challenge. In a model of aerosolized lipopolysaccharide-induced inflammation, where iNOS gene expression is increased, 1400W inhibited the increased neutrophilia. These data suggest that the compound has been administered using an appropriate dosing regimen for iNOS inhibition in the rat lung. In conclusion, it appears that constitutive, not inducible, NOS isoforms are important in NO production in models of allergic inflammation, which questions whether there is a role for iNOS inhibitors as therapy for the treatment of asthma.
The marked diminution in the number of circulating eosinophils, which has been shown to occur during acute bacterial infections, is a distinctive aspect of eosinophil physiology and of the host response to acute infection. The mouse rendered eosinophilic by infection with trichinosis provides a suitable model for study of the eosinopenic response induced by acute inflammation. The alterations in eosinophil dynamics associated with acute inflammatory reactions in trichinous mice were studied with pneumococcal abscesses, with Escherichia coli pyelonephritis, with Coxsackie viral pancreatitis, and with acute subcutaneous inflammation due to turpentine. Each of these stimuli of acute inflammation markedly suppressed the eosinophilia of trichinosis. This suggests that the eosinopenia is a response to the acute inflammatory process rather than the response to a specific type of pathogen. These studies apply quantitative techniques to ascertain the effects of acute inflammation on eosinophil production in bone marrow and on distribution of eosinophils in the peripheral tissues. From these observations, it is apparent that the initial response to acute inflammation includes a rapid drop in numbers of circulating eosinophils, a rapid accumulation of eosinophils at the periphery of the inflammatory site, and an inhibition of egress of eosinophils from the bone marrow. With prolongation of the inflammatory process, inhibition of eosinopoiesis occurs.
Immune inflammation (II) arises on the basis of immunopathological mechanisms and acquires certain qualitative and quantitative features. It develops in a sensitized host following a specific immune response. Several kinds of II are to be distinguished differing from each other by the prevalence of disorders in cellular or humoral immunity, the pattern of the antigen, involvement in the response of immunoglobulins of different classes, complement components and a set of mediators. According to Sell's scheme, six immunopathological mechanisms are distinguished which underlie the development of early (like immediate type hypersensitivity) or late (like delayed type hypersensitivity) immune inflammation. Sometimes humoral and cellular mechanisms alternate in II which is reflected in the morphological picture of inflammation. This is illustrated by an example of the study of tissue inflammatory reactions in the synovial membrane in rheumatoid arthritis. Immune inflammation shows a trend to self-reproduction and continuous course with periods of remission and exacerbation of different durations. Timely recognition of immune inflammation is important both theoretically and practically.
OBJECTIVE: Arterial stiffness, an independent determinant of cardiovascular risk, is regulated by both structural and functional factors, including endothelium-derived nitric oxide. Endothelial dysfunction is associated with acute and chronic systemic inflammation. However, the role of systemic inflammation in arterial stiffening has not been determined. The aim of this study was to investigate the relationship between inflammation and arterial stiffness in patients with antineutrophil cytoplasmic antibody-associated systemic vasculitis (AASV) as a model of systemic inflammation. METHODS: Thirty-one patients with AASV (15 with active disease) and 32 age-matched controls were studied. Pulse wave velocity (PWV) and the augmentation index (AIx) were assessed noninvasively and related to serum levels of C-reactive protein (CRP), interleukin-6, and tumor necrosis factor alpha. RESULTS: In subjects with active disease, the AIx, PWV, and level of CRP were elevated compared with that in controls (mean +/- SEM 31 +/- 3% versus 22 +/- 2% [P = 0.003], 9.2 +/- 0.7 versus 7.5 +/- 0.3 meters/second [P = 0.03], and 16.0 +/- 4.0 versus 1.1 +/- 0.1 mg/liter [P < 0.001], respectively). However, PWV and the AIx were not significantly different between patients with disease in remission and controls (8.0 +/- 0.5 versus 7.5 +/- 0.3 meters/second and 19 +/- 3% versus 22 +/- 2%, respectively). The CRP level was positively correlated with both PWV and the AIx. Multiple regression analysis indicated that age, mean arterial pressure (MAP), and CRP were independently related to PWV, and that age, MAP, CRP, sex, and heart rate were associated with the AIx. CONCLUSION: These data indicate that AASV is associated with increased arterial stiffness, and that stiffness correlates with the degree of active inflammation.
BACKGROUND: Nerve growth factor (NGF) exerts an important functional impact on the pathogenesis of allergic diseases. Data obtained in animal models of allergic bronchial asthma indicate that NGF alters sensory nerve function and promotes allergic inflammation, bronchial hyper-reactivity, and airway obstruction. OBJECTIVE: To further delineate the effects of NGF on airway inflammation, we employed a transgenic (tg) animal model of allergic inflammation and asthma. METHODS: NGF-tg mice, which overexpress NGF in Clara cells of the airways, were compared with wild-type (wt) littermates regarding their ability to mount IgE-related airway inflammatory responses. Mice were sensitized intraperitoneally to ovalbumin (OVA) and locally challenged via the airways according to established protocols. RESULTS: NGF-tg mice displayed enhanced levels of OVA-specific IgE antibody titres after repeated OVA aerosol exposure. In the airways, increased numbers of eosinophils were detected. These results were confirmed to be NGF specific, because similar results were obtained following local application of NGF into the airways of wt mice. The effect of NGF was partly mediated via neuropeptides, as treatment of OVA-sensitized NGF-tg mice with the dual neurokinin (NK) receptor NK-1/NK-2 antagonist partly prevented enhanced airway inflammation. CONCLUSION: The present data indicate an important functional role of NGF in allergic airway inflammation and point to an involvement of tachykinins as mediators of NGF effects.