Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “INFLAMMATION”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 973 records · Page 54Linked to original sources
PubMed2000

Unaltered peripheral excitatory actions of nociceptin contrast with enhanced spinal inhibitory effects after carrageenan inflammation: an electrophysiological study in the rat.

Nociceptin (orphanin FQ) is the endogenous agonist of the opioid receptor-like (ORL-1) receptor. The actions of this peptide have been studied extensively at a number of sites with diverse actions being reported. Here, in a rat model of peripheral inflammation, we examine the effects of nociceptin on the responses of dorsal horn neurones when applied directly to the spinal cord and, in separate studies, into the peripheral receptive fields in the hindpaw of the halothane anaesthetized rat. As changes in the receptor density and expression of the message for nociceptin have been reported after inflammation we have compared these actions to previously reported effects in normal animals. The dose-dependent inhibitory actions of nociceptin on C-fibre evoked responses and input (measures of presumed pre-synaptic excitability) are increased 3-4 h after inflammation whereas its inhibitory effects on post-synaptic mechanisms (wind-up) remain unchanged. These inhibitory effects were partly reversible by high doses of naloxone. This increased potency of nociceptin after inflammation is consistent with an increased receptor density in the superficial spinal cord. In contrast, the peripheral administration of nociceptin produced dose-dependent excitations of dorsal horn neurones and a degree of sensitization to mechanical stimuli. This peripheral action was unchanged after inflammation. These diverse site-dependent actions of nociceptin further emphasize the complexities of this novel opioid system.

Animals↗
PubMed2001

Differential contributions of NMDA and non-NMDA receptors to spinal Fos expression evoked by superficial tissue and muscle inflammation in the rat.

The role of N-methyl-D-aspartate (NMDA) and non-NMDA receptors in the spinal cord in the transmission of nociceptive afferents from superficial tissue and muscle was studied by examining the effects of NMDA or non-NMDA receptor antagonists on Fos expression in the spinal dorsal horn. Muscle inflammation was induced by injection of turpentine oil into the gastrocnemius muscle, whereas superficial tissue inflammation was induced by an intraplantar injection of turpentine oil into the hindpaw. The NMDA receptor antagonist DL-2-amino-5-phosphonovaleric acid (AP-5), the non-NMDA receptor antagonist 6,7-dinitroquinoxaline-2,3-dione (DNQX) or normal saline were intrathecally administered 15 min before an intramuscular or intraplantar injection of turpentine oil. Muscle inflammation evoked expression of Fos-like immunoreactive neurons staining in neurons that were predominantly distributed in the middle portions of laminae I-II(outer) and the lateral portions of laminae V-VI of the ipsilateral dorsal horn at the spinal L(4)-L(5). DNQX, but not AP-5, significantly reduced the total number of Fos-like immunoreactive neurons evoked by muscle inflammation. In contrast, superficial tissue inflammation evoked expression of Fos-like immunoreactive neurons in the medial portions of laminae I-II(outer) and V-VI of the ipsilateral dorsal horn at the spinal L(4)-L(5) that was blocked by AP-5, but not by DNQX. Injection of normal saline did not influence the numbers of Fos-LI neurons. These results indicate that different glutamate receptors in the dorsal horn of the spinal cord may mediate nociceptive input from superficial tissue (particularly skin) and muscle. DNQX receptors may mediate transmission of nociceptive information originating in muscle, while NMDA receptors may preferentially mediate transmission of nociceptive information originating in skin.

Afferent Pathways↗
PubMed1998

A capsaicin-receptor antagonist, capsazepine, reduces inflammation-induced hyperalgesic responses in the rat: evidence for an endogenous capsaicin-like substance.

In the present study, the presence of an endogenous capsaicin-like substance and the role of capsaicin receptors in nociception during inflammation were assessed using Fos immunohistochemistry and the paw-withdrawal test in rats. Intradermal injection of carrageenan in the hind-paw produced inflammation in the foot pad, increased the number of cells exhibiting Fos-like immunoreactivity in the dorsal horn of the spinal cord, and decreased the paw-withdrawal latency. Intradermal injection of capsazepine, a capsaicin-receptor antagonist, significantly reduced the number of cells exhibiting Fos-like immunoreactivity, significantly increased the paw-withdrawal latency, but did not decrease inflammation induced by carrageenan injection. Intradermal injection of capsaicin or formalin also increased Fos-positive neurons. Capsaicin- or formalin-induced Fos expression was reduced in both cases by pretreatment of capsazepine, but to a much lesser extent for formalin. The capsazepine inhibition of carrageenan inflammation-induced hyperalgesic responses strongly suggests that an endogenous capsaicin-like substance is released in inflamed tissues and produces nociceptive neural impulses by acting on capsaicin receptors present on sensory neurons. Furthermore, our results indicate that capsaicin receptors take part only in generating nociceptive signals in sensory neurons, but not in activating the inflammation-promoting cells.

Animals↗
PubMed2003

Unilateral hindpaw inflammation induces bilateral activation of the locus coeruleus and the nucleus subcoeruleus in the rat.

Several lines of evidence have shown that unilateral hindpaw inflammation produces activation of the locus coeruleus (LC) and the nucleus subcoeruleus (SC), resulting in descending modulation of nociceptive processing in the dorsal horn. However, it is unclear if the LC/SC is activated unilaterally or bilaterally following the development of unilateral hindpaw inflammation. The present study was designed to clarify this question. For the induction of unilateral hindpaw inflammation, lambda carrageenan (2.0mg in 0.15ml saline) was injected subcutaneously into the plantar surface of the left hindpaw. Four hours after carrageenan injection, in the LC/SC both ipsilateral and contralateral to the inflamed paw, the number of Fos-positive cells increased significantly in carrageenan-injected rats when compared to vehicle (saline)-injected and untreated control rats. The Fos expression in the LC/SC was equivalent bilaterally in the carrageenan-injected rats, as well as in vehicle-injected and untreated control rats. For nociceptive testing, the paw withdrawal latency, which measures cutaneous hyperalgesia in response to thermal stimuli, was determined in rats receiving a unilateral lesion of the LC/SC either ipsilateral or contralateral to the inflamed paw. Two and a half hours after the induction of inflammation, in both groups of rats with unilateral lesion, paw withdrawal latencies decreased significantly in the LC/SC-lesioned rats. However, there was no significant difference in paw withdrawal latencies between the LC/SC-lesioned rats and sham-operated rats, indicating that unilateral activation of the LC/SC is sufficient for modulating nociceptive processing in the dorsal horn. These results suggest that unilateral hindpaw inflammation induces bilateral activation of the LC/SC.

Animals↗
PubMed2000

Divergent effects of hormone therapy on serum markers of inflammation in postmenopausal women with coronary artery disease on appropriate medical management.

OBJECTIVES: The goal of our study was to determine whether hormone therapy alters markers of inflammation in postmenopausal women with chronic stable coronary artery disease (CAD) on appropriate medical management. BACKGROUND: Hormone therapy reduces some markers of inflammation associated with atherosclerosis risk (cell adhesion molecules) but increases levels of another marker of inflammation--C-reactive protein-in healthy postmenopausal women. METHODS: Ten women (average age 66 years; range 59 to 76 years) with CAD on medical management (including aspirin [9], statin lipid-lowering therapy [7], angiotensin-converting enzyme inhibitors [3]) were randomly assigned to conjugated equine estrogens 0.625 mg (combined with medroxyprogesterone acetate 2.5 mg daily in five women with uterus intact) or placebo(s) daily for one month with crossover to the alternate therapy after one month off of hormone treatment in a double-blind study. At the end of each treatment phase, the following markers of inflammation were measured in serum: interleukin-6, C-reactive protein, E-selectin, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and matrix metalloproteinase-9. RESULTS: Hormone therapy significantly lowered serum levels of cell adhesion molecules E-selectin (46.9+/-18.3 vs. 56.3+/-20.6 ng/mL, p = 0.006), intercellular adhesion molecule-1 (282+/-74 vs. 304+/-78 ng/mL, p = 0.013) and vascular cell adhesion molecule-1 (605+/-218 vs. 657+/-214 ng/mL, p = 0.01) but increased levels of matrix metalloproteinase-9 (648+/-349 vs. 501+/-285 ng/mL, p = 0.02). Interleukin-6 (4.33+/-4.78 vs. 3.04+/-1.47 pg/mL, p = 0.283) and C-reactive protein (0.88+/-1.13 vs. 0.61+/-0.50 mg/dL, p = 0.358) were not significantly elevated on hormone therapy compared with placebo values. CONCLUSIONS: Hormone therapy has divergent effects on serum markers of inflammation in women with CAD. Reduction in levels of cell adhesion molecules may reduce attachment of white blood cells to the vessel wall, but increases in matrix metalloproteinase-9 within the vessel wall could digest and weaken fibrous caps of vulnerable plaques, thus provoking thrombosis.

Aged↗
PubMed2003

Acute systemic inflammation enhances endothelium-dependent tissue plasminogen activator release in men.

OBJECTIVES: The purpose of this study was to investigate in vivo the effects of acute systemic inflammation on the endogenous fibrinolytic capacity in men. BACKGROUND: Systemic inflammation and endogenous fibrinolysis play a major role in the pathogenesis of coronary artery disease. Although previous studies have shown impaired endothelium-dependent vasomotor function, the effects of inflammation on the endothelial release of the fibrinolytic factor tissue plasminogen activator (t-PA) are unknown. METHODS: In a double-blind randomized placebo-controlled crossover trial, we administered a mild inflammatory stimulus, Salmonella typhi vaccine, or saline placebo to eight healthy men on two separate occasions. Six hours after vaccination, blood flow and plasma fibrinolytic variables were measured in both arms during intrabrachial infusions of bradykinin (40 to 1,000 pmol/min), acetylcholine (5 to 20 microg/min), and sodium nitroprusside (2 to 8 microg/min). RESULTS: Compared with placebo, the S. typhi vaccination caused a rise in white cell count (11.1 +/- 0.5 x10(9)/l vs. 7.9 +/- 0.8 x10(9)/l; p = 0.004) and plasma interleukin-6 concentrations (6.9 +/- 1.4 pg/ml vs. 1.6 +/- 0.4 pg/ml; p = 0.01) in addition to a significant augmentation of t-PA antigen (45 +/- 9 ng/100 ml/min at peak dose vs. 24 +/- 8 ng/100 ml/min at peak dose; p = 0.016, analysis of variance) and activity (104 +/- 15 IU/100 ml/min vs. 54 +/- 12 IU/100 ml/min; p = 0.006, analysis of variance) release during bradykinin infusion. Forearm blood flow increased in a dose-dependent manner after bradykinin, acetylcholine and sodium nitroprusside infusions (p < 0.001), but this was unaffected by vaccination. CONCLUSIONS: Our results showed that acute systemic inflammation augmented local forearm t-PA release in men, which suggests that acute inflammation may invoke a protective response by enhancing the acute endogenous fibrinolytic capacity in healthy men. Further studies are needed to clarify whether this response is impaired in patients with cardiovascular disease.

Acetylcholine↗
PubMed1997

Efficacy of diclofenac eyedrops in preventing postoperative inflammation and long-term cystoid macular edema. Italian Diclofenac Study Group.

PURPOSE: To compare the efficacy and tolerance of diclofenac 0.1% eyedrops with a regimen that included a brief course of steroids in the treatment of postoperative inflammation after extracapsular cataract surgery and posterior chamber intraocular lens implantation. A second objective was to compare the efficacy of diclofenac 0.1% eyedrops in the same patients and control group in preventing cystoid macular edema (CME). SETTING: Eight university/hospital centers and one company in Italy. METHODS: The multicenter, controlled, randomized, prospective, double-blind study included 281 patients. All were evaluated at baseline, at surgery, and after 1, 5, 36, 67, and 140 days. Postoperative inflammation was measured by the clinical assessment of inflammation: conjunctival hyperemia, ciliary flush, Tyndall effect, and cells in the anterior chamber. Fluorescein angiography was performed to evaluate the presence/absence of CME before surgery and after 36 and 140 days. RESULTS: During follow-up, no differences in intraoperative pressure were observed within or between groups or between operated and fellow eyes. No statistically significant between-group differences in postoperative inflammation were found. After 36 days, angiographic CME was found in 9 patients (6.43%) in the diclofenac group and 20 (15.15%) in the control group (P = .033) with a relative risk for developing CME of 0.40 (CI95 0.19 to 0.84). At the end of follow-up, it was found in 4 patients in the diclofenac group (3.31%) and 10 (9.26%) in the control group (P = .05) with a relative risk of 0.36 (CI95 0.12 to 0.90). CONCLUSION: Diclofenac sodium was as effective as the control regimen in controlling postoperative inflammation after cataract surgery. It also had a protective effect on the development of angiographic CME after 36 and 140 days.

Aged↗
PubMed2002

Inflammation and the development of pancreatic cancer.

OBJECTIVE: Pancreatic cancer has an extremely poor prognosis and the cellular mechanisms contributing to pancreatic cancer are relatively unknown. The goals of this review are to present the epidemiological and experimental data that supports inflammation as a key mediator of pancreatic cancer development, to explain how inflammatory pathways may create an environment that supports tumor formation, and to discuss how the use of novel agents directed at these pathways may be used for the treatment of pancreatic malignancy. SUMMARY BACKGROUND DATA: Inflammation has been identified as a significant factor in the development of other solid tumor malignancies. Both hereditary and sporadic forms of chronic pancreatitis are associated with an increased risk of developing pancreatic cancer. The combined increase in genomic damage and cellular proliferation, both of which are seen with inflammation, strongly favors malignant transformation of pancreatic cells. Cytokines, reactive oxygen species, and mediators of the inflammatory pathway (e.g., NF-kappaB and COX-2) have been shown to increase cell cycling, cause loss of tumor suppressor function, and stimulate oncogene expression; all of which may lead to pancreatic malignancy. Anti-cytokine vaccines, inhibitors of pro-inflammatory NF-kappaB and COX-2 pathways, thiazolidinediones, and anti-oxidants are potentially useful for the prevention or treatment of pancreatic cancer. Redirection of experimental interests toward pancreatic inflammation and mechanisms of carcinogenesis may identify other novel anti-inflammatory agents or other ways to screen for or prevent pancreatic cancer. CONCLUSION: Pancreatic inflammation, mediated by cytokines, reactive oxygen species, and upregulated pro-inflammatory pathways, may play a key role in the early development of pancreatic malignancy.

Carcinoma↗
PubMedDate not supplied

Inflammation induced by latex of Calotropis procera--a new model to evaluate anti-inflammatory drugs.

Latex of Calotropis procera was studied for its inflammatory reactions using pedal oedema and air pouch models of inflammation in rats. Subcutaneous injection of aqueous solution (0.1 ml of 1%) of dry latex (DL) into the plantar surface of paw produced significant inflammation. Maximum inflammatory response was obtained 1 h after the injection and was maintained for a further 1 h. The inflammatory response was accompanied by an increase in vascular permeability that reached its maximum within 15 min. Inflammation was also induced in the 6-day-old rat air pouch by injecting a 2.5% solution of DL. The latter model was characterized for the exudate volume and its protein concentration, and wet and dry weights of granuloma. A time-course study indicated that both the exudate volume and the weight of granuloma were at maximum on day 5 after DL injection while the protein concentration peaked on the third day. Further, the two models were also studied for the anti-inflammatory effect of various drugs. It was observed that in the pedal oedema model, phenylbutazone was more effective than prednisolone while almost complete inhibition was produced by mepyramine and cyproheptadine. On the other hand, in the air pouch model, prednisolone was more effective than phenylbutazone in inhibiting the inflammation. Thus, the DL-induced inflammation in different models could be used to evaluate anti-inflammatory drugs.

Animals↗
PubMed2003

Minimal persistent inflammation, an emerging concept in the nature and treatment of allergic rhinitis: the possible role of leukotrienes.

OBJECTIVE: To review the emerging concept of minimal persistent inflammation in allergic rhinitis and its implications for therapy. DATA SOURCES: Relevant clinical studies in the English language were reviewed. STUDY SELECTION: Material was taken from academic/scholarly journals. RESULTS: Accumulating evidence suggests that allergic rhinitis is a chronic inflammatory disease instead of a disease of acute symptoms. An approach to the therapy for allergic rhinitis should consider that even when symptoms are absent, a minimal level of persistent inflammation may persist. To prevent unexpected exacerbations, the treatment strategy may need to include managing subclinical persistent inflammation. Therapeutic options addressing the major inflammatory elements in allergic rhinitis, including eosinophils, the cysteinyl leukotrienes, and histamine, must be evaluated as management strategies that can achieve effective control. Traditional medications include intranasal corticosteroids, antihistamines, and immunotherapy. Recently, a leukotriene receptor antagonist has been approved for major rhinitis symptoms (congestion, rhinorrhea, sneezing, and pruritus), suggesting a new option for the treatment of allergic rhinitis. CONCLUSIONS: Because of the possible presence of a minimal persistent inflammation during rhinitis patients' asymptomatic periods, it is important to consider a prophylactic approach to treating allergic rhinitis to prevent or reduce exacerbations during an acute increase in allergen. In light of the advances in the understanding of the pathogenesis of allergic rhinitis, agents must be considered based on their safety, efficacy, and ability to deal with underlying inflammation as well as symptom relief.

Histamine↗
PubMed2002

High-density lipoprotein-associated apolipoprotein A-I: the missing link between infection and chronic inflammation?

The etiology of chronic immuno-inflammatory diseases including rheumatoid arthritis (RA), multiple sclerosis (MS), systemic lupus erythematosus (SLE), and atherosclerosis is far from being elucidated. It is generally accepted that multiple factors are involved in the development of such pathologies, including factors of genetic susceptibility that interact in complex ways with diverse environmental factors, i.e. gender, nutrition, environment, etc. Furthermore, infection has often been pinpointed as playing a causal role. However, no distinctive pattern has yet emerged from the tremendous number of compiled results that would provide a generally acceptable hypothesis of the etiology of immuno-inflammatory diseases, and the possibility of a persistent antigenic stimulus arising from an infection cannot be confirmed or refuted. At the cellular level, chronic inflammation is characterized by the infiltration of immuno-inflammatory cells into the target tissue, which mostly precedes tissue damage. At the inflammatory site, monocytes and T lymphocytes are in close proximity. We have demonstrated that contact-mediated activation of monocytes by stimulated T lymphocytes is a major stimulus triggering the production of large amounts of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1beta (IL-1beta) whose importance in chronic inflammation is well known. We recently established that high-density lipolipoprotein (HDL)-associated apolipoprotein (apo) A-I is a specific inhibitor of cytokine production in monocyte-macrophages upon contact with stimulated T cells. HDL-associated apo A-I is a negative acute-phase protein, i.e. a protein whose level is lowered by more than 25% during the acute phase. This review aims at highlighting the fact that HDL-associated apo A-I might play the role of a constitutive anti-inflammatory factor. The decrease of plasma levels of HDL-associated apo A-I upon acute inflammation may be a sign of the possible development of chronic inflammation, i.e. individuals presenting with risk factors might develop chronic inflammatory diseases after infection. We thus hypothesize that HDL-associated apo A-I might be the missing link between infection and chronic inflammation.

Acute-Phase Reaction↗
PubMed2000

Airway inflammation in asthma and perennial allergic rhinitis. Relationship with nonspecific bronchial responsiveness and maximal airway narrowing.

BACKGROUND: Eosinophilic airway inflammation is the hallmark of asthma, but it has also been reported in other conditions such as allergic rhinitis. We have tested whether the analysis of cells and chemicals in sputum can distinguish between patients with mild allergic asthma, those with allergic rhinitis, and healthy controls. The relationship between inflammation markers in sputum and nonspecific bronchial hyperresponsiveness to methacholine (BHR) (PD20 and maximal response plateau [MRP] values) was also evaluated. METHODS: We selected 31 mild asthmatics and 15 rhinitis patients sensitized to house-dust mite. As a control group, we studied 10 healthy subjects. Every subject underwent the methacholine bronchial provocation test (M-BPT) and sputum induction. Blood eosinophils and serum ECP levels were measured. Sputum cell differentials were assessed, and eosinophil cationic protein (ECP), tryptase, albumin, and interleukin (IL)-5 levels were measured in the entire sputum supernatant. RESULTS: Blood eosinophils and serum ECP levels were higher in asthma patients and rhinitis than in healthy controls, but no difference between asthma patients and rhinitis patients was found. Asthmatics had higher eosinophil counts and higher ECP and tryptase levels in sputum than rhinitis patients or control subjects. Sputum albumin levels were higher in asthmatics than in controls. Rhinitis patients exhibited higher sputum eosinophils than healthy controls. An association between sputum eosinophil numbers and MPR values (r= -0.57) was detected, and a trend toward correlation between sputum ECP levels and PD20 values (r= -0.47) was found in the rhinitis group, but not in asthmatics. No correlation between blood eosinophilic inflammation and lung functional indices was found. CONCLUSIONS: Induced sputum is an accurate method to study bronchial inflammation, allowing one to distinguish between rhinitis patients and mildly asthmatic patients. The fact that no relationship was detected between sputum inflammation and BHR suggests that other factors, such as airway remodeling, may be at least partly responsible for BHR in asthma.

Adolescent↗
PubMed2000

Polymorphisms at the glutathione S-transferase, GSTP1 locus: a novel mechanism for susceptibility and development of atopic airway inflammation.

A common feature of environmental irritants is their ability to cause local inflammation which could alter airway function. The principal targets of such injury are the epithelial cells lining the airway passages and the lower respiratory gas-exchange areas. While host atopy is a recognized risk factor for airway inflammation, atopy alone cannot cause asthma. We hypothesize that susceptibility to persistent airway inflammation in atopic individuals is characterized by an inherited deficiency in the effectiveness of detoxification of inhaled irritants and products of oxidative stress such as reactive oxygen species (ROS). Our case-control studies show that polymorphisms at the glutathione S-transferase, GSTP1, locus on chromosome 11q13 may account for variation in host response to oxidative stress, a key component of airway inflammation. Frequency of the GSTP1 Val/Val genotype is reduced in atopic subjects compared with nonatopic subjects. Trend analysis also shows a significant decrease of GSTP1 Val/Val (with parallel increase of GSTP1 Ile/Ile) genotype frequency with increasing severity of airflow obstruction/bronchial hyperresponsiveness. The implication of specific polymorphisms at the GSTP1 locus in airway inflammation is entirely novel: however, GST are recognized as a supergene family of enzymes critical in 1) cell protection from the toxic products of ROS-mediated reactions, 2) modulation of eicosanoid synthesis.

Bronchial Hyperreactivity↗
PubMed2006

Prostaglandin E2 is required for ultraviolet B-induced skin inflammation via EP2 and EP4 receptors.

Keratinocytes are the major target of sunlight, and they produce prostaglandin (PG) E(2) upon ultraviolet (UV) exposure. Although indomethacin, one of cyclooxygenase inhibitors, is known to suppress UV-induced acute skin inflammation, it remains uncertain whether endogenous PGE(2) is responsible for UV-induced skin inflammation, and which subtype of PGE(2) receptors mediates this process. UV-induced skin inflammation was investigated by using genetically and pharmacologically PGE(2) receptor-deficient mice. We applied UV-induced skin inflammation model to genetical and pharmacological PGE(2) receptor-deficient mice. We exposed UVB on these mice at 5 kJ/m(2), and examined the ear swelling and the histological findings. We also measured the blood flow using a laser doppler device to assess the intensity of UVB-induced inflammatory change. The UV-induced ear swelling at 48 h after exposure was significantly reduced in EP2(-/-), EP4(-/-) or wild-type mice treated with the EP4 antagonist compared to control mice. Consistently, inflammatory cell infiltration into the local skin, and local blood flow after UV exposure were significantly reduced by EP2 or EP4 signaling blockade. These data suggest that PGE(2)-EP2/EP4 signaling is mandatory in UV-induced acute skin inflammation, presumably by enhancing blood flow in the microenvironment.

Animals↗
PubMed2001

Early interleukin 4-dependent response can induce airway hyperreactivity before development of airway inflammation in a mouse model of asthma.

In experimental models of bronchial asthma with mice, airway inflammation and increase in airway hyperreactivity (AHR) are induced by a combination of systemic sensitization and airway challenge with allergens. In this report, we present another possibility: that systemic antigen-specific sensitization alone can induce AHR before the development of inflammation in the airway. Male BALB/c mice were sensitized with ovalbumin (OVA) by a combination of intraperitoneal injection and aerosol inhalation, and various parameters for airway inflammation and hyperreactivity were sequentially analyzed. Bronchial response measured by a noninvasive method (enhanced pause) and the eosinophil count and interleukin (IL)-5 concentration in bronchoalveolar lavage fluid (BALF) gradually increased following the sensitization, and significant increase was achieved after repeated OVA aerosol inhalation along with development of histologic changes of the airway. In contrast, AHR was already significantly increased by systemic sensitization alone, although airway inflammation hardly developed at that time point. BALF IL-4 concentration and the expression of IL-4 mRNA in the lung reached maximal values after the systemic sensitization, then subsequently decreased. Treatment of mice with anti-IL-4 neutralizing antibody during systemic sensitization significantly suppressed this early increase in AHR. In addition, IL-4 gene-targeted mice did not reveal this early increase in AHR by systemic sensitization. These results suggest that an immune response in the lung in an early stage of sensitization can induce airway hyperreactivity before development of an eosinophilic airway inflammation in BALB/c mice and that IL-4 plays an essential role in this process. If this early increase in AHR does occur in sensitized human infants, it could be another therapeutic target for early prevention of the future onset of asthma.

Allergens↗
PubMed2004

NF-kappaB functions as a tumour promoter in inflammation-associated cancer.

The causes of sporadic human cancer are seldom recognized, but it is estimated that carcinogen exposure and chronic inflammation are two important underlying conditions for tumour development, the latter accounting for approximately 20% of human cancer. Whereas the causal relationship between carcinogen exposure and cancer has been intensely investigated, the molecular and cellular mechanisms linking chronic inflammation to tumorigenesis remain largely unresolved. We proposed that activation of the nuclear factor kappaB (NF-kappaB), a hallmark of inflammatory responses that is frequently detected in tumours, may constitute a missing link between inflammation and cancer. To test this hypothesis, we studied the Mdr2-knockout mouse strain, which spontaneously develops cholestatic hepatitis followed by hepatocellular carcinoma, a prototype of inflammation-associated cancer. We monitored hepatitis and cancer progression in Mdr2-knockout mice, and here we show that the inflammatory process triggers hepatocyte NF-kappaB through upregulation of tumour-necrosis factor-alpha (TNFalpha) in adjacent endothelial and inflammatory cells. Switching off NF-kappaB in mice from birth to seven months of age, using a hepatocyte-specific inducible IkappaB-super-repressor transgene, had no effect on the course of hepatitis, nor did it affect early phases of hepatocyte transformation. By contrast, suppressing NF-kappaB inhibition through anti-TNFalpha treatment or induction of IkappaB-super-repressor in later stages of tumour development resulted in apoptosis of transformed hepatocytes and failure to progress to hepatocellular carcinoma. Our studies thus indicate that NF-kappaB is essential for promoting inflammation-associated cancer, and is therefore a potential target for cancer prevention in chronic inflammatory diseases.

ATP Binding Cassette Transporter, Subfamily B↗
PubMed1999

In vitro prostanoid release from spinal cord following peripheral inflammation: effects of substance P, NMDA and capsaicin.

1. Spinal prostanoids are implicated in the development of thermal hyperalgesia after peripheral injury, but the specific prostanoid species that are involved are presently unknown. The current study used an in vitro spinal superfusion model to investigate the effect of substance P (SP), N-methyl-d-aspartate (NMDA), and capsaicin on multiple prostanoid release from dorsal spinal cord of naive rats as well as rats that underwent peripheral injury and inflammation (knee joint kaolin/carrageenan). 2. In naive rat spinal cords, PGE2 and 6-keto-PGF1alpha, but not TxB2, levels were increased after inclusion of SP, NMDA, or capsaicin in the perfusion medium. 3. Basal PGE2 levels from spinal cords of animals that underwent 5-72 h of peripheral inflammation were elevated relative to age-matched naive cohorts. The time course of this increase in basal PGE2 levels coincided with peripheral inflammation, as assessed by knee joint circumference. Basal 6-keto-PGF1alpha levels were not elevated after injury. 4. From this inflammation-evoked increase in basal PGE2 levels, SP and capsaicin significantly increased spinal PGE2 release in a dose-dependent fashion. Capsaicin-evoked increases were blocked dose-dependently by inclusion of S(+) ibuprofen in the capsaicin-containing perfusate. 5. These data suggest a role for spinal PGE2 and NK-1 receptor activation in the development of hyperalgesia after injury and demonstrate that this relationship is upregulated in response to peripheral tissue injury and inflammation.

6-Ketoprostaglandin F1 alpha↗
PubMed2002

Therapeutic effect of the endogenous fatty acid amide, palmitoylethanolamide, in rat acute inflammation: inhibition of nitric oxide and cyclo-oxygenase systems.

1. The anti-inflammatory activity of the endogenous fatty acid amide palmitoylethanolamide and its relationship to cyclo-oxygenase (COX) activity, nitric oxide (NO) and oxygen free radical production were investigated in the rat model of carrageenan-induced acute paw inflammation and compared with the nonsteroidal anti-inflammatory drug (NSAID) indomethacin. 2. Palmitoylethanolamide (1, 3, 5, 10 mg kg(-1); p.o.) and indomethacin (5 mg kg(-1); p.o.) were administered daily after the onset of inflammation for three days and the paw oedema was measured daily; 24 h after the last dose (fourth day) the rats were killed and the COX activity and the content of nitrite/nitrate (NO(2)(-)/NO(3)(-)), malondialdehyde (MDA), endothelial and inducible nitric oxide synthase (eNOS and iNOS) were evaluated in the paw tissues. 3. Palmitoylethanolamide had a curative effect on inflammation, inhibiting the carrageenan-induced oedema in a dose- and time-dependent manner. This effect was not reversed by the selective CB(2) receptor antagonist (N-[(1S)-endo-1,3,3-trimethylbicyclo[2.2.1]heptan-2yl]-5-(4-chloro-3-methylphenyl)-1-(4-methylbenzyl)pyrazole-3 carboxamide) (SR144528), 3 mg kg(-1) p.o. On the fourth day after carrageenan injection, COX activity and the level of NO(2)(-)/NO(3)(-), eNOS and MDA were increased in the inflamed paw, but iNOS was not present. Palmitoylethanolamide (10 mg kg(-1)) and indomethacin markedly reduced these increases. 4. Our findings show, for the first time, that palmitoylethanolamide has a curative effect in a model of acute inflammation. The inhibition of COX activity and of NO and free radical production at the site of inflammation might account for this activity.

Acute Disease↗