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PubMed2005

Ultrafine carbon black particles cause early airway inflammation and have adjuvant activity in a mouse allergic airway disease model.

To gain more insight into the mechanisms of particulate matter (PM)-induced adjuvant activity, we studied the kinetics of airway toxicity/inflammation and allergic sensitization to ovalbumin (OVA) in response to ultrafine carbon black particles (CBP). Mice were exposed intranasally to OVA alone or in combination with different concentrations of CBP. Airway toxicity and inflammation were assessed at days 4 and 8. Immune adjuvant effects were studied in the lung draining peribronchial lymph nodes (PBLN) at day 8. Antigen-specific IgE was measured at days 21 and 28, whereas allergic airway inflammation was studied after OVA challenges (day 28). Results show that a total dose of 200 microg CBP per mouse, but not 20 microg or 2 microg, induced immediate airway inflammation. This 200 microg CBP was the only dose that had immune adjuvant activity, by inducing enlargement of the PBLN and increasing OVA-specific production of Th2 cytokines (IL-4, IL-5, and IL-10). The immune adjuvant activity of 200 microg CBP dosing was further examined. Whereas increased OVA-specific IgE levels in serum on day 21 confirms systemic sensitization, this was further supported by allergic airway inflammation after challenges with OVA. Our data show a link between early airway toxicity and adjuvant effects of CBP. In addition, results indicate that local cytokine production early after exposure to CBP is predictive of allergic airway inflammation. In addition this model appears suitable for studying the role of airway toxicity, inflammation and other mechanisms of particle adjuvant activity, and predicting the adjuvant potential of different particles.

Administration, Intranasal↗
PubMed1994

Response of alpha 2-macroglobulin messenger ribonucleic acid expression to acute inflammation in the testis is different from the response in the liver and brain.

Recent studies from this laboratory have shown that Sertoli cells derived from 20-day-old rats and cultured in vitro synthesize and secrete a nonspecific protease inhibitor that is structurally and immunologically similar to serum alpha 2-macroglobulin (alpha 2-MG). In contrast to its serum homologue, the testicular alpha 2-MG is not an acute-phase protein in the rat since its protein concentration in the rete-testis fluid does not increase in response to inflammation. In the present study we examined the expression of alpha 2-MG mRNA in the rat testis in comparison to that in the brain and liver following induced inflammation. alpha 2-MG mRNA in the testis did not respond to induced inflammation, whereas its protein concentration in serum and its mRNA level in the brain and liver increased significantly in 20-day-old inflamed rats. In 8-day-old rat testis, where the blood-testis barrier is not yet formed, alpha 2-MG mRNA expression also did not respond to induced inflammation. The mRNA expression of clusterin, another authentic Sertoli cell protein whose secretion appears to be closely related to cell-cell interactions in the seminiferous epithelium, was shown to be unaffected by induced inflammation in the testis, brain, and liver. In view of the unexpected differential expression of alpha 2-MG mRNA to induced inflammation in the testis and liver, we sought to examine whether Sertoli cell alpha 2-MG would respond to FSH and testosterone (T), the major regulators of testicular function. Interestingly, expression of alpha 2-MG and clusterin mRNA in the Sertoli cell was not regulated by FSH, T, or a combination of FSH and T. Since there is an intimate morphological relationship between Sertoli cells and germ cells, we next examined the effect of germ cell-conditioned medium (GCCM) on Sertoli cell alpha 2-MG and clusterin mRNA expression. It was noted that GCCM caused a dose-dependent stimulation of alpha 2-MG and inhibition of clusterin mRNA expression in Sertoli cells, respectively. Therefore, our studies have shown that the regulatory mechanism that modulates the expression of alpha 2-MG mRNA in the rat testis is different from its counterpart in the brain and liver.

Aging↗
PubMed2000

Inducible nitric oxide synthase in the rat testis: evidence for potential roles in both normal function and inflammation-mediated infertility.

In vitro data have indicated that nitric oxide (NO) inhibits Leydig cell testosterone production, suggesting that NO may play a role in the suppression of steroidogenesis and spermatogenic function during inflammation. Consequently, we investigated expression of the inflammation-inducible isoform of NO synthase (iNOS) in the inflamed adult rat testis and the ability of a broad-spectrum inhibitor of NO production, L-nitro-L-arginine methyl ester, to prevent Leydig cell dysfunction during inflammation. Unexpectedly, immunohistochemical and mRNA data established that iNOS is expressed constitutively in Leydig cells and in a stage-specific manner in Sertoli, peritubular, and spermatogenic cells in the normal testis. Expression was increased in a dose-dependent manner in all these cell types during lipopolysaccharide (LPS)-induced inflammation. In noninflamed testes, treatment with the NO synthase inhibitor reduced testicular interstitial fluid formation and testosterone production without any effect on serum LH levels. Administration of the inhibitor did not prevent the suppression of testicular interstitial fluid and testosterone production that occurs within 6 h after LPS treatment. Collectively, these data indicate a novel role for iNOS in autocrine or paracrine regulation of the testicular vasculature, Leydig cell steroidogenesis, and spermatogenesis in the normal testis. The data suggest that increased NO is not the major cause of acute Leydig cell dysfunction in the LPS-treated inflammation model, although a role for NO in this process cannot be excluded, particularly at other time points. Moreover, up-regulation of iNOS may contribute to the seminiferous epithelium damage caused by LPS-induced inflammation.

Animals↗
PubMed1999

The effect of a sciatic nerve block on the development of inflammation in carrageenan injected rats.

UNLABELLED: Neurogenic inflammation may participate in postoperative inflammatory pain. We evaluated, in the rat, the influence of a short and prolonged sciatic nerve block on carrageenan-induced inflammation, the time course of which may be compared to postoperative inflammation. A catheter was placed on the right sciatic nerve and injected with 0.5% bupivacaine with epinephrine (0.2 mL): one injection in the Short Block Group, and four injections performed at 90-min intervals in the Prolonged Block Group. In all groups, the two hind paws were then injected with carrageenan. The development of inflammation was evaluated in both hind paws by measurement of paw circumference (PC) before, and 1, 2, 3, 4, 6, and 24 h after carrageenan injection. Temperature of both hind paws was evaluated at the same time points. The vocalization threshold to paw pressure test (VTPP) of both hind paws was evaluated at 6, 8, 10, 12, and 24 h after carrageenan injection. The left hind paw was used for the Control Group. A Sham Group had a catheter placed on the sciatic nerve and injected with normal saline. Inflammation developed in the Control Group with a maximum increase of PC (32%) and temperature (14%) 4 h after carrageenan injection and a maximal reduction of VTPP (44%) at 6 h, reflecting mechanical allodynia. A similar evolution was observed in the Sham Group. In the Short Block Group, the nerve block did not influence the PC, the paw temperature, or the VTPP when compared with the Control Group. In the Prolonged Block Group, when compared with the Control Group, the increased PC was reduced throughout the 24 h (P < 0.0001). The maximal increase in PC at 4 h was limited to 23%, as compared with the precarrageenan value. This effect on PC did not persist at 24 h. Paw temperature was increased (P = 0.07) throughout the study in the Prolonged Block Group, as compared with the Control Group. The VTPP reduction was still limited in the Prolonged Block Group at 24 h, as compared with the Control Group (P < 0.0001). We conclude that a prolonged sciatic nerve block limits carrageenan-induced increase in PC and, subsequently, mechanical allodynia at 24 h in rats. IMPLICATIONS: Our study has shown that a prolonged (6 h) but not a short sciatic nerve block (90 min) can limit edema and related pain after carrageenan-induced inflammation in rat.

Anesthetics, Local↗
PubMed2000

Intestinal inflammation and morphine tolerance alter the interaction between morphine and clonidine on gastrointestinal transit in mice.

BACKGROUND: Morphine and clonidine show synergy or antagonism inhibiting gastrointestinal transit depending on their proportion and level of effect. Their interaction during morphine tolerance and intestinal inflammation were assessed. METHODS: Gastrointestinal transit in mice was evaluated with charcoal and antitransit effects expressed as percent mean values +/- SEM. Tolerance was induced with a morphine pellet (75 mg) implanted for 72 h, and inflammation with intragastric croton oil. Dose-response curves for morphine and clonidine alone and combined at a 1:1 potency ratio were obtained, and doses producing a 50% and 60% inhibition were calculated (ED50, ED60). Interaction was established by isobolograms, interaction indexes, and analysis of variance. RESULTS: In naive and tolerant mice, the combination induced linear dose-response curves up to the ED60 and then reached a plateau. In naive mice, ED50 values were as follows: morphine 1.52 +/- 0.15 mg/kg, clonidine 0.09 +/- 0.008 mg/kg, and combined 0.506 +/- 0.084 mg/kg (0.478 +/- 0.08 mg/kg morphine plus 0.028 +/- 0.004 mg/kg clonidine). During tolerance, ED50 values were as follows: morphine 9.73 +/- 0.8 mg/kg, clonidine 0.09 +/- 0.007 mg/kg, combination 0.131 +/- 0.09 mg/kg (morphine 0. 13 +/- 0.09 mg/kg plus clonidine 0.0013 +/- 0.0005 mg/kg). In both groups, the interaction was synergistic up to the ED60 and antagonistic thereafter; synergy was enhanced during tolerance. During inflammation, ED50 values were as follows: morphine 0.17 +/- 0.04 mg/kg, clonidine 0.015 +/- 0.006 mg/kg, combined 0.62 +/- 0.04 mg/kg (morphine 0.568 +/- 0.04 mg/kg plus clonidine 0.052 +/- 0.004 mg/kg); thus, potencies of morphine and clonidine increased 9.3 and 7.1 times, while the combination remained unaltered. Moreover, inflammation transformed synergy into antagonism. CONCLUSIONS: The interaction between morphine and clonidine was significantly altered during tolerance and inflammation. During tolerance, synergy was present up to 60% effect and then became antagonistic. Inflammation converted synergy to antagonism. A common pathway in signal transduction could partially explain the results.

Analgesics↗
PubMed2006

Inflammation markers in young post-myocardial patients exhibiting various expressions of classic coronary risk factors.

OBJECTIVE: We investigated inflammation markers in young post-myocardial infarction patients exhibiting various expressions of classical risk factors. METHODS: Forty-one male patients with high (n=20) and low (n=21) expression of classical risk factors (risk of coronary events calculated by the prospective cardiovascular Munster study program high or low, respectively), on average 44 years old, who were in the stable phase after myocardial infarction (on average 20.5 months after myocardial infarction) were included in the study. The control group consisted of 25 healthy, age-matched men. The following inflammation markers were measured: leukocyte count, high-sensitive C-reactive protein, interleukin-6, tumor necrosis factor-alpha, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, selectin-P and selectin-E. RESULTS: No differences in the levels of leukocytes, high-sensitive C-reactive protein, tumor necrosis factor-alpha, intracellular adhesion molecule-1, vascular cellular adhesion molecule-1, selectin-P and selectin-E were found between the group of patients and the controls. In contrast, interleukin-6 was significantly (P<0.01) elevated in the group of patients with high [2.5 (1.9-5.3) ng/ml] and low [3.2 (1.5-8.4) ng/ml] expression of risk factors compared with the controls [1.4 (0.9-2.3) ng/ml]. Significantly, there was no difference in interleukin-6 between the two groups of patients. CONCLUSIONS: We did not find differences in inflammation markers between young post-myocardial infarction patients with or without classical risk factors. Thus, it seems that the presence of (treated) risk factors or their absence does not affect the levels of inflammation markers in the stable period after myocardial infarction. Importantly, we found similarly elevated interleukin-6 in both groups of patients, most probably indicating slight local vascular inflammation. Interleukin-6 appears to be the most suitable marker of vascular inflammation in post-myocardial infarction patients who are aggressively treated pharmacologically.

Adult↗
PubMed2003

Nitric oxide in allergic airway inflammation.

PURPOSE OF REVIEW: Exhaled nitric oxide has been proposed as a useful noninvasive marker of airway inflammation in asthma. Great efforts have been made to standardize the methodology for exhaled nitric oxide measurement in both children and adults. As a consequence there is now an opportunity to establish the precise relationship between exhaled nitric oxide, atopy and airway inflammation, and to investigate whether or not there is a role for the measurement of exhaled nitric oxide in the management of patients with asthma. RECENT FINDINGS: A number of recent studies have investigated the relationship between exhaled nitric oxide and airway inflammation in asthma measured directly, using sputum induction, bronchoalveolar lavage and endobronchial biopsy. These measurements suggest that exhaled nitric oxide reflects eosinophilic airway inflammation in asthma, although there is no evidence for any relationship between exhaled nitric oxide and other airway inflammatory cells. Exhaled nitric oxide levels were found to be higher in atopic compared with nonatopic groups. These levels, however, are further elevated in atopic patients with asthma, suggesting that exhaled nitric oxide is not simply a marker of atopy. Although there is little evidence to support the routine use of measurement of exhaled nitric oxide in the management of patients with asthma, it may prove to be useful in assessing adherence to treatment with inhaled corticosteroids, or in the identification of patients in whom respiratory symptoms are associated with eosinophilic airway inflammation. SUMMARY: There is good evidence that exhaled nitric oxide reflects eosinophilic airway inflammation in asthma. Well designed, long-term studies are needed to evaluate whether the addition of exhaled nitric oxide measurements to clinical and lung function assessment results in improved asthma control.

Asthma↗
PubMed2003

Sclerosing inflammation in the orbit and in the pterygopalatine and infratemporal fossae.

PURPOSE: To describe two cases with sclerosing inflammation in the orbit and in the pterygopalatine and infratemporal fossae and to review the literature of head and neck idiopathic inflammation. METHODS: Interventional case series. Two clinical case reports of sclerosing inflammation in the orbits and in the pterygopalatine and infratemporal fossae are presented. A review of the literature and discussion was performed. RESULTS: Both patients had histologic findings typical of chronic orbital sclerosing inflammation, including mature lymphocytes associated with dense collagen deposition and occasional lymphoid follicles. Bone erosion was present in one patient. CONCLUSIONS: The clinical findings of this case series concur with the literature that idiopathic inflammation can be found simultaneously in the orbit and in the infratemporal and pterygopalatine fossae. These cases of idiopathic inflammation are often clinically indistinguishable from malignant neoplasms.

Adult↗
PubMed2004

Inflammation as a target for prostate cancer chemoprevention: pathological and laboratory rationale.

PURPOSE: We review the literature addressing a potential causal role for chronic or recurrent inflammation or infection in the development of prostate cancer. MATERIALS AND METHODS: A literature search was conducted using MEDLINE to identify articles on chronic inflammation as a risk factor for cancer, particularly prostate cancer. RESULTS: A causal role for chronic or recurrent inflammation or infection in the development of prostate cancer has yet to be proven. Inflammation may contribute to carcinogenesis by 1 or more of several potentially interrelated mechanisms, including 1) the elaboration of cytokines and growth factors that favor tumor cell growth, 2) induction of cyclooxygenase-2 in macrophages and epithelial cells, and 3) generation of mutagenic reactive oxygen and nitrogen species. Chronic inflammation in the form of stromal and epithelial infiltrates of lymphocytes and histiocytes is extremely common in the peripheral zone of the prostate where most cancers arise. Although differences in histology and terminology exist for these inflammatory and atrophic lesions, as a group they often display evidence of epithelial proliferation. Heterogeneous expression of the GSTP1 gene in such lesions has been proposed as evidence for susceptibility to oxidative damage, thereby providing fertile ground for carcinogenesis. CONCLUSIONS: Although the cumulative evidence demonstrates that chronic inflammation may be a legitimate target for chemopreventive efforts, more study is needed to prove its etiological role in prostate cancer.

Causality↗
PubMed2005

Potential of superparamagnetic iron oxide in the differential diagnosis of metastasis and inflammation in bone marrow: experimental study.

RATIONALE AND OBJECTIVES: The utility of ferucarbotran for the diagnosis of bone metastases was investigated using tumor-implanted rabbits. The potential of ferucarbotran in the differential diagnosis of metastasis and inflammation was also investigated. METHODS: Twelve rabbits were divided into 2 groups (tumor and inflammation groups). Six rabbits of tumor group were inoculated with VX2 tumor cell suspension, and the 6 rabbits of the inflammation group were inoculated with 10% croton oil in the bone marrow of the right femur. All rabbits were imaged using a clinical MRI system. Signal intensity in the bone marrow of the right femur was measured in each rabbit before and after the intravenous injection of 8 micromol Fe/kg of ferucarbotran. As a control, the signal intensity in the bone marrow of the left femur (the normal, intact femur) was measured in each rabbit. The change in signal intensity of each group was compared statistically. After MRI imaging, the femora were removed, and sections were prepared for microscopic examination. RESULTS: Signal intensity in the right femur of the tumor group did not change after injection, although that of the inflammation group and the control group decreased. In the histologic findings, tumors were widely spread in the right femur of the tumor group. The infiltration of pseudoeosinocytes was induced in the right femur of the inflammation group. CONCLUSIONS: This animal study showed that ferucarbotran was useful to detect bone marrow tumors. In addition, ferucarbotran may have potential in the differential diagnosis of bone metastasis and some kinds of inflammation.

Animals↗
PubMed2006

Lipoxins and annexin-1: resolution of inflammation and regulation of phagocytosis of apoptotic cells.

Phagocytosis of apoptotic cells plays a pivotal role in developmental processes and in the resolution of inflammation. Failed or delayed clearance of apoptotic cells can result in chronic inflammation. Furthermore, clearance of apoptotic cells leads to release of anti-inflammatory cytokines. Recent evidence has shown that endogenous mediators can regulate such processes. In this article, we will review the recognition and signaling mechanisms involved in the phagocytosis of apoptotic cells as well as the role of endogenous compounds that play a relevant role in the modulation of inflammation. The first of these endogenous local mediators to be described are lipoxins (LXs). LXs and aspirin-triggered LXs (ATLs) are considered to act as "braking signals" in inflammation, limiting the entrance of leukocytes to the site of inflammation through inhibition of neutrophil and eosinophil trafficking. LXs are actively involved in resolution of inflammation, stimulating nonphlogistic phagocytosis of apoptotic cells by macrophages. LXA4 and ATLs elicit cellular responses by interacting with a G protein -coupled receptor (ALXR) that is expressed in various cell types. ALXR, originally identified as a low-affinity N-formyl-methionyl-leucyl-phenylalanine receptor-like 1, can bind pleiotropic ligands, i.e., both lipid and peptides, including the glucocorticoid-inducible protein, annexin-1. Interestingly, a role for annexin-1 in phagocytosis has recently emerged. Understanding the role and mechanism of the powerful anti-inflammatory and proresolution actions of endogenous compounds can be a useful tool in the development of potential therapeutics in resolving inflammatory diseases.

Animals↗
PubMed2004

Is targeting Toll-like receptors and their signaling pathway a useful therapeutic approach to modulating cytokine-driven inflammation?

Cytokine-driven inflammation and tissue destruction is a common theme of chronic inflammatory diseases such as rheumatoid arthritis, Crohn's disease, ulcerative colitis, psoriasis, chronic obstructive pulmonary disease, and atherosclerosis. Research over the last two decades demonstrated the importance of cytokines that are not only expressed chronically but also are capable of signaling at sites of chronic inflammation. Cytokines thus regulate major pathological processes that include inflammation, angiogenesis, tissue remodeling, and fibrosis. This research led to the identification of key cytokines involved in these processes, two of which, tumor necrosis factor-alpha and interleukin-1, have also been successfully targeted in the clinic. However, what triggers and maintains cytokine gene expression in chronic inflammation remains a mystery. In this article, we review current progress in the understanding of cytokine-driven inflammation and discuss current evidence implicating Toll-like receptors (TLRs), recently identified as the receptors recognizing self versus non-self molecular patterns, in the regulation of cytokine-driven inflammation. Whether targeting TLRs and their downstream signaling pathway will prove to be a successful approach for the treatment of these devastating diseases remains to be determined.

Animals↗
PubMed1993

Neurophysiological evidence for increased kappa opioidergic control of spinal cord neurons in rats with unilateral inflammation at the ankle.

The role of the endogenous kappa opioid system in the control of neuronal activity has been studied in the spinal cord of normal rats and in rats with Freund's adjuvant induced unilateral inflammation of the ankle under barbiturate anaesthesia. During recordings from neurons with ankle input the kappa receptor agonist U50,488H and/or the kappa antagonist nor-binaltorphamine were administered ionophoretically using multibarrel electrodes. In most neurons tested U50,488H reduced the responses evoked by pressure applied across the ankle whereas smaller proportions of neurons showed increased activity or were not affected. The kappa opioid antagonist nor-binaltorphamine affected more neurons in rats with inflammation than in control rats. Ongoing activity was increased in 7 of 19 (37%) neurons in control rats, in 16 of 24 (67%) neurons in the acute phase of inflammation (2 days post inoculation) and in 15 of 23 (65%) neurons in the chronic phase of inflammation (16-20 days post inoculation). During application of nor-binaltorphamine in control rats, the responses to pressure were increased in 9 cells (36%), reduced in 7 cells (28%) and unaffected in 9 cells (36%). In the acute phase of inflammation significantly more neurons (11 of 15, 73%) showed enhanced responses to pressure during ionophoresis of nor-binaltorphamine but not in the chronic phase. These results show that spinal cord neurons with ankle input are influenced by the endogenous kappa opioid system particularly under inflammatory conditions. The upregulation of this system under inflammatory conditions may serve to counteract inflammation-induced hyperexcitability.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1989

Effect of turpentine-induced inflammation on the disposition kinetics of propranolol, metoprolol, and antipyrine in the rat.

Plasma concentrations after oral administration of the high extraction drug propranolol are increased in patients and animals with inflammation. This could be due to increased serum propranolol binding, but also to decreased first-pass metabolism. We studied the pharmacokinetics of 3 drugs in control rats and in rats with turpentine-induced inflammation: propranolol, which is bound extensively to alpha 1-acid glycoprotein (alpha 1-AGP); metoprolol, another high extraction drug, but which is negligibly bound to alpha 1-AGP; and antipyrine, a low extraction drug, not bound to serum proteins. After IV administration of propranolol in rats with inflammation, systemic clearance, volume of distribution, and free fraction decreased, and the area under the curve (AUC) increased, whereas the half-life did not change. As the systemic clearance of a high extraction drug such as propranolol depends on hepatic blood flow only, a fall in hepatic blood flow or transition to a low extraction situation should be postulated. After oral administration of propranolol, the AUC was increased 20-fold in rats with inflammation; as the decrease in free fraction was only 4-fold, it can be concluded that a considerable decrease in hepatic intrinsic clearance was present. For metoprolol, in contrast to propranolol, after IV administration, no changes in pharmacokinetic parameters as a result of inflammation were observed. After oral administration, the AUC was increased about 4 times in rats with inflammation; as metoprolol is only negligibly bound to serum proteins, the increase in AUC can be attributed to a decrease in hepatic intrinsic clearance.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Oral↗
PubMed1969

Enhancement of inflammation and histamine formation by actinomycin D.

1. An inflammation model developed in other laboratories was used in this study. Mice given endotoxin intranasally developed lung inflammation which progresses in intensity for several days. Lung weight is a satisfactory measure of inflammation.2. In lungs of mice treated intranasally with endotoxin, histidine decarboxylase was activated within 6 hr, before lung weight had increased substantially. Enzyme activity was near maximal at 24 hr but had dropped by 48 hr, at which time inflammation was increasing. The data are consistent with an early role for histamine in mediating inflammation, but not with an essential role in the later stages.3. When actinomycin D, an inhibitor of RNA synthesis, was mixed with endotoxin solution and given to mice intranasally, both lung inflammation and histidine decarboxylase activation were markedly enhanced at 24 and 48 hr, relative to effects produced by endotoxin alone.4. Evidence is presented that intranasal instillation of endotoxin into mice increases histamine formation in lung in vivo.5. We previously found protein synthesis inhibitors, the only drugs shown capable of blocking histidine decarboxylase activation, to be powerful anti-inflammatory agents. Now we have found that actinomycin D, the only drug shown capable of enhancing histidine decarboxylase activation, to be strongly pro-inflammatory. These observations support a causative role for histamine in slowly-developing inflammation, and also provide a rigorous test for the participation of other mediator candidates.

Animals↗
PubMed2004

Up-regulation of endothelin receptor function and mRNA expression in airway smooth muscle cells following Sephadex-induced airway inflammation.

The hypothesis that up-regulation of bronchial constrictor endothelin receptors in airway smooth muscle cells may contribute to hyperreactivity during airway inflammation was tested in the present study by quantitative endothelin receptor mRNA analysis and functional responses in ring segments of rat trachea and bronchi. Real time reverse transcription polymerase chain reaction was used to quantify endothelin receptor expression in rat airway smooth muscle cells following Sephadex-induced inflammation. Compared with controls, Sephadex-induced airway inflammation caused a significant increase (3.9 times P<0.05) of endothelin receptor type B mRNA expression in bronchial smooth muscle cells, but not in tracheal smooth muscle cells. Functional myograph studies of bronchial and tracheal ring segments without epithelium (mechanically denuded) revealed an increase of the maximum contractile effects of endothelin-1 (a dual agonist for both endothelin type A and B receptors) and sarafotoxin 6c (a selective agonist for endothelin B receptors) in bronchial smooth muscle cells in Sephadex-induced inflammation, but not in tracheal smooth muscle cells. The enhanced maximal responses of bronchial smooth muscle cells to endothelin-1 and sarafotoxin 6c in Sephadex-induced inflammation support our molecular findings and hence imply a role for endothelin B receptors in airway hyperreactivity during airway inflammation.

Animals↗
PubMed2001

Inflammation enhances mu-opioid receptor transcription and expression in mice intestine.

Opioid receptors (ORs) and their mRNA are present in the central and peripheral nervous systems of mammals and in different peripheral tissues, including the gut. Using a model of croton oil-induced (CO) intestinal inflammation in mice, we have shown a 6-fold increase in the potency of the antitransit and antisecretory effects of mu-OR agonists, mediated by peripheral ORs. We postulate that the enhanced effects are mediated by an increase in the expression of intestinal OR. We used jejunum (stripped of the mucosal layer) from mice with CO-induced intestinal inflammation and, as control subjects, saline-treated animals (SS). We evaluated the quantity of mu-OR mRNA determined by a competitive reverse-transcriptase polymerase chain reaction; the levels of mu-OR protein by Western blot immunoassay, and the localization and number of cells expressing mu-OR using immunohistochemistry. The results show a significant increase of mu-OR mRNA (7.7-fold) and receptor protein (3-fold) during intestinal inflammation. Inflammation also induced a 64.3% increase in the number of neurons expressing mu-OR immunoreactivity in the myenteric plexus but not in the submucosal plexus. Our results show that intestinal inflammation enhances the transcription and translation of mu-OR mRNA, thus explaining the increased potency of mu-opioids during inflammation.

Animals↗
PubMed2006

Intranasal exposure to bacterial superantigens induces airway inflammation in HLA class II transgenic mice.

Staphylococcus aureus is widely prevalent in the nasopharynges of healthy individuals (carriers) but can also cause serious infections. S. aureus can elaborate a variety of superantigen exotoxins in "carrier" or "pathogenic" states. Streptococcus pyogenes can also colonize the nasopharynx and elaborate superantigens. Unlike the acute effects of superantigen exotoxins absorbed through the gut or vaginal mucosa, little is known regarding the pathogenesis of superantigens entering through the intranasal route. In the current study, we evaluated the local and systemic effects of staphylococcal enterotoxin B (SEB) and streptococcal pyrogenic exotoxin A (SPEA) delivered through the intranasal route. Superantigens were administered intranasally on multiple occasions, and experimental animals were sacrificed on day 8 for experimental analyses. SEB-induced airway inflammation was more pronounced for HLA-DR3 transgenic mice than for BALB/c mice, consistent with bacterial superantigens binding more efficiently to human than murine major histocompatibility complex class II. The nature of the airway inflammation in HLA-DR3 mice was determined by the concentration of SEB applied intranasally. Low concentrations (20 ng) induced eosinophilic airway inflammation as well as eosinophil degranulation, whereas intranasal exposure to higher concentrations (2,000 ng) resulted in neutrophilic airway inflammation, permanent airway destruction, toxic shock, and mortality. SEB-induced eosinophilic inflammatory response was enhanced in signal transducer and activator of transcription (STAT)-4-deficient HLA-DQ8 transgenic mice with defective interleukin-12 signaling. Intranasal administration of SPEA induced airway inflammation and systemic immune activation in HLA-DQ8 transgenic mice. In conclusion, repeated chronic intranasal exposure to bacterial superantigens causes airway inflammation and systemic immune activation.

Administration, Intranasal↗