Local Release Of Inflammatory Mediators Research Articles

<I>Helicobacter pylori</I> infection and dermatological diseases

Helicobacter pylori (H. Pylori), microaerophilic spiral-shaped Gram-negative bacteria which colonize the gastric mucosa of human population, is the leading causal factor in the development of a whole range of diseases of the gastroduodenal region (chronic gastritis, gastric and duodenal ulcer disease, MALT lymphoma and gastric adenocarcinoma). Since the discovery of H. pylori infection and the identification of its leading role in the development of a range of gastroenterological diseases, researchers have begun to actively study the potential trigger significance of this pathogen in the development of extragastric pathology. At the epidemiological level, H. pylori infection has been shown to be frequently associated with skin diseases such as rosacea, acne, chronic urticaria and psoriasis, although the clinical significance of these associations remains clouded. In fact, recent meta-analytic studies (2019–2024) demonstrate an increased risk of developing the above diseases in H. pylori-infected individuals with odds ratios ranging from 1.19 to 3.00. On the other hand, not all studies have showed that eradication therapy of this microorganism helps reduce the clinical severity of symptoms of skin diseases, which is hypothetically explained only by the trigger role of infection within the complex pathogenesis. In a modern light, such associations can be viewed in terms of pathogenetic findings through the implementation of the syndrome of increased epithelial permeability (SIEP). The chronic gastritis caused by H. pylori infection is believed to lead to increased permeability of the epithelial lining of the stomach, as well as the walls of the mucosal vessels and a higher exposure of bacterial and nutritional antigens in the systemic circulation, which can induce both local release of inflammatory mediators in tissues and systemic immunological reactions (autoimmune and inflammatory processes, formation of molecular mimicry-induced immune complexes and cross-reactive antibodies).

Pentobarbital may protect against neurogenic inflammation after surgery via inhibition of substance P release from peripheral nerves of rats

The inflammatory response related to surgery is considered surgical inflammation. Most anesthetic agents directly or indirectly suppress the immune response. However, the intravenous anesthetics pentobarbital and ketamine were reported to inhibit the lipopolysaccharide-induced inflammatory response such as cytokines formation. Neurogenic inflammation is inflammation originating from the local release of inflammatory mediators, such as substance P (SP), by primary afferent neurons after noxious stimuli like surgery. Thus, in this study, we examined whether pentobarbital and ketamine suppress SP release from cultured dorsal root ganglion (DRG) neurons. DRG cells were dissected from male Wistar rats. Released SP was measured by radioimmunoassay. We demonstrated that higher concentrations of pentobarbital (100–1,000 μM) significantly inhibited capsaicin (100 nM)-induced, but not high K+ (50 mM)-induced, SP release from DRG cells, although a high concentration of ketamine (1 mM) did not. This study revealed that pentobarbital functions between the activation of vanilloid receptor subtype 1 (TRPV1) receptors, to which capsaicin selectively binds, and the opening of voltage-operated Ca2+ channels (VOCC) in the nerve endings. Therefore, the anti-inflammatory action of pentobarbital is mediated through different mechanisms than those of ketamine. Thus, the inhibitory effect of pentobarbital on SP release from peripheral terminals may protect against neurogenic inflammation after surgery.

Lipid emulsion mitigates impaired pulmonary function induced by limb ischemia/reperfusion in rats through attenuation of local cellular injury and the subsequent systemic inflammatory

BackgroundLimb ischemia/reperfusion causes inflammation and elicits oxidative stress that may lead to local tissue damage and remote organ such as lung injury. This study investigates pulmonary function after limb ischemia/reperfusion and the protective effect of a lipid emulsion (Intralipid).MethodsTwenty-four rats were divided into three groups: sham operation group (group S), ischemia/reperfusion group (group IR), and lipid emulsion treatment group (group LE). limb ischemia/reperfusion was induced through occlusion of the infrarenal abdominal aorta for 3 h. The microvascular clamp was removed carefully and reperfusion was provided for 3 h.ResultsThe mean arterial pressure in group LE was higher than group IR during the reperfusion period (P = 0.024). The heart rate of both group LE and IR are significantly higher than group S during the ischemia period(P < 0.001, P < 0.001, respectively). The arterial oxygen pressure of group LE was significantly higher than group IR (P = 0.003), the arterial carbon dioxide pressure of group LE were lower than that of group IR (P = 0.005). The concentration of plasma interleukin-6, tumor necrosis factor-α and malondialdehyde in group LE were significantly lower than group IR (P < 0.001, P = 0.009 and 0.029, respectively). The plasma superoxide dismutase activity in group LE was significantly higher than group IR (P = 0.029). The myeloperoxidase activity in lung tissues of group LE was significantly less than group IR (P = 0.046). Both muscle and lung in group IR were damaged seriously, whereas lipid emulsion (Intralipid) effectively reversed the damage. In summary, Intralipid administration resulted in several beneficial effects as compared to group IR, such as the pulmonary gas exchange and inflammatory.ConclusionsThe ischemic/reperfusion injury of limb muscles with resultant inflammatory damage to lung tissue can be mitigated by administration of a lipid emulsion (Intralipid, 20%, 5 ml/kg). The mechanisms attenuating such a physiological may be attributed to reduction of the degree of limb injury through a decrease in the release of local inflammatory mediators, a reduction of lipid peroxidation, and a blunting of the subsequent remote inflammatory response.

Segmental Hyperperfusion in Lobar Pneumonia Visualized with Respiratory-gated Four-Dimensional Pulmonary Perfusion Positron Emission Tomography–Computed Tomography

A 64-year-oldman underwent a respiratory-gated four-dimensional pulmonary perfusion positron emission tomography (PET)/computed tomography (CT) for preoperative regional lung function quantification. This was performed after intravenous administration of Gamacroaggregated albumin (1–3). At the time of imaging, he had a productive cough, fever, and subsequent clinical diagnosis of bronchopneumonia. Images demonstrated an area of hyperperfusion localized to an area of dense collapse/consolidative change in the lateral segment of the right middle lobe (Figure 1 and supplemental video E1). The abnormality was also clearly apparent on the nonattenuation correction images, excluding an attenuation artifact. Studies have typically documented matched ventilation–perfusion or reverse mismatch phenomenon in pneumonia (4). Although occlusive obstruction of lobar airways is usually accompanied by reflex hypoxic vasoconstriction, the local release of inflammatory mediators with vasodilatory properties with infection results in failure of this mechanism and shunting leading to hypoxia (5). The histopathologic correlate is the red hepatization phase of lobar pneumonia. Tc-macroaggregated albumin single-photon emission computed tomography/CT had also been performed in this patient, but no corresponding perfusion abnormality was found. Although this was performed 72 hours earlier, the CT abnormality was similar; we contend that in addition to the superior imaging characteristics of PET, the absence of respiratory gating and attenuation correction contributed to lack of abnormality on single-photon emission computed tomography. The higher spatial and temporal resolution of PET combined with four-dimensional acquisition (6) provides a major advance in image quality and may improve our understanding of pulmonary physiology in a spectrum of diseases. n

The role of histamine in neurogenic inflammation

The term 'neurogenic inflammation' has been adopted to describe the local release of inflammatory mediators, such as substance P and calcitonin gene-related peptide, from neurons. Once released, these neuropeptides induce the release of histamine from adjacent mast cells. In turn, histamine evokes the release of substance P and calcitonin gene-related peptide; thus, a bidirectional link between histamine and neuropeptides in neurogenic inflammation is established. The aim of this review is to summarize the most recent findings on the role of histamine in neurogenic inflammation, with particular regard to nociceptive pain, as well as neurogenic inflammation in the skin, airways and bladder.

5-HT induces temporomandibular joint nociception in rats through the local release of inflammatory mediators and activation of local β adrenoceptors

The 5-hydroxytryptamine (serotonin, 5-HT) is an important inflammatory mediator found in high levels in the synovial fluid of the temporomandibular joint (TMJ) of patients with inflammatory pain. In this study, we used the nociceptive behavior responses, measured as flinching the head and rubbing the orofacial region, as a nociceptive assay. We demonstrated that the local blockade of the 5-HT3 receptor and β1 or β2-adrenoceptors, the depletion of norepinephrine in the sympathetic terminals and the local inhibition of cyclooxygenase significantly reduced 5-HT-induced TMJ nociception. These results demonstrated that 5-HT induces nociception in the TMJ region by the activation of β1 and β2 adrenoceptors located in the TMJ region and local release of sympathetic amines and prostaglandins. Therefore, the high levels of 5-HT in the synovial fluid of patients with TMJ inflammatory pain may contribute to TMJ pain by similar mechanisms.

Management of Neuropathic Pain with Methylprednisolone at the Site of Nerve Injury

Peripheral nerve blocks with methylprednisolone may provide effective pain therapy by decreasing ectopic neuronal discharge and the release of local inflammatory mediators at the site of nerve injury. In this study, we aimed to compare the efficacy of lidocaine alone with a combination of depo-methylprednisolone plus lidocaine in the management of neuropathic pain due to peripheral nerve damage. Randomized, double-blind comparator trial. Group control (N = 44) received 0.5% lidocaine and group methylprednisolone (N = 44) received 80 mg depo-methylprednisolone + 0.5% lidocaine proximal to the site of nerve injury with a total amount of 10-20 mL solution according to the type of peripheral nerve block with nerve stimulator. Demographic data, preblock numerical rating scales (NRSs), the Leeds assessment of neuropathic symptoms and signs (LANSS(0) ) score, accompanying symptoms, and analgesic requirements were recorded. Postblock NRS scores were noted following peripheral nerve block and after 3 months. LANSS(1) , accompanying symptoms, and analgesic requirements were also reevaluated 3 months after the injection. Demographic data, preblock NRS (8 ± 1.5 and 8.1 ± 1.2, respectively), postblock NRS (2.1 ± 1.2 and 2.4 ± 1.4, respectively), LANSS(0) (18.4 ± 2.2 and 18.2 ± 2.1, respectively), and accompanying symptoms were comparable between groups. Scores for the methylprednisolone group were significantly improved at 3-month postblock for NRS (2 ± 1.4 vs 5.2 ± 1.7) and LANSS(1) scores (4.14 ± 2.7 vs 14.1 ± 2.8), accompanying symptoms, and analgesic requirements (P < 0.0001). Our results suggest that peripheral nerve block with 80 mg depo-methylprednisolone plus 0.5% lidocaine provides effective management in the treatment of neuropathic pain due to peripheral nerve damage.

F250 MANAGEMENT OF NEUROPATHIC PAIN WITH METHYLPREDNISOLONE AT THE SITE OF NERVE INJURY

Objective. Peripheral nerve blocks with methylprednisolone may provide effective pain therapy by decreasing ectopic neuronal discharge and the release of local inflammatory mediators at the site of nerve injury. In this study, we aimed to compare the efficacy of lidocaine alone with a combination of depo-methylprednisolone plus lidocaine in the management of neuropathic pain due to peripheral nerve damage. Design. Randomized, double-blind comparator trial Setting. Group control (N = 44) received 0.5% lidocaine and group methylprednisolone (N = 44) received 80 mg depo-methylprednisolone + 0.5% lidocaine proximal to the site of nerve injury with a total amount of 10–20 mL solution according to the type of peripheral nerve block with nerve stimulator. Outcome Measures. Demographic data, preblock numerical rating scales (NRSs), the Leeds assessment of neuropathic symptoms and signs (LANSS0) score, accompanying symptoms, and analgesic requirements were recorded. Postblock NRS scores were noted following peripheral nerve block and after 3 months. LANSS1, accompanying symptoms, and analgesic requirements were also reevaluated 3 months after the injection. Results. Demographic data, preblock NRS (8 1.5 and 8.1 1.2, respectively), postblock NRS (2.1 1.2 and 2.4 1.4, respectively), LANSS0 (18.4 2.2 and 18.2 2.1, respectively), and accompanying symptoms were comparable between groups. Scores for the methylprednisolone group were significantly improved at 3-month postblock for NRS (2 1.4 vs 5.2 1.7) and LANSS1 scores (4.14 2.7 vs 14.1 2.8), accompanying symptoms, and analgesic requirements (P < 0.0001). Conclusions. Our results suggest that peripheral nerve block with 80 mg depo-methylprednisolone plus 0.5% lidocaine provides effective management in the treatment of neuropathic pain due to peripheral nerve damage.

MDA5 and PTPN2, two candidate genes for type 1 diabetes, modify pancreatic β-cell responses to the viral by-product double-stranded RNA

β-Cell destruction in type 1 diabetes (T1D) is at least in part consequence of a ‘dialog’ between β-cells and immune system. This dialog may be affected by the individual's genetic background. We presently evaluated whether modulation of MDA5 and PTPN2, two candidate genes for T1D, affects β-cell responses to double-stranded RNA (dsRNA), a by-product of viral replication. These genes were selected following comparison between known candidate genes for T1D and genes expressed in pancreatic β-cells, as identified in previous array analysis. INS-1E cells and primary fluorescence-activated cell sorting-purified rat β-cells were transfected with small interference RNAs (siRNAs) targeting MDA5 or PTPN2 and subsequently exposed to intracellular synthetic dsRNA (polyinosinic–polycitidilic acid—PIC). Real-time RT–PCR, western blot and viability assays were performed to characterize gene/protein expression and viability. PIC increased MDA5 and PTPN2 mRNA expression, which was inhibited by the specific siRNAs. PIC triggered apoptosis in INS-1E and primary β-cells and this was augmented by PTPN2 knockdown (KD), although inhibition of MDA5 did not modify PIC-induced apoptosis. In contrast, MDA5 silencing decreased PIC-induced cytokine and chemokine expression, although inhibition of PTPN2 induced minor or no changes in these inflammatory mediators. These findings indicate that changes in MDA5 and PTPN2 expression modify β-cell responses to dsRNA. MDA5 regulates inflammatory signals, whereas PTPN2 may function as a defence mechanism against pro-apoptotic signals generated by dsRNA. These two candidate genes for T1D may thus modulate β-cell apoptosis and/or local release of inflammatory mediators in the course of a viral infection by acting, at least in part, at the pancreatic β-cell level.

TRPA1: irritant detector of the airways

The respiratory tract is innervated by primary afferent sensory neurons that respond to mechanical and chemical stimuli (Taylor-Clark & Undem, 2006). The majority of these neurons are unmyelinated C-fibres that respond to noxious chemicals, such as reactive oxygen species (ROS), the main irritants of tear gas, air pollution and burning vegetation (Kollarik & Undem, 2004). Activation of airway sensory neurons leads to centrally mediated afferent reflexes including shortness of breath, cough and changes in breathing patterns. Sensory neuron activation also triggers the local release of inflammatory mediators that sensitize the airways to future chemical and mechanical stimuli. While normally protective, airway inflammation can exacerbate respiratory disorders such as asthma, emphysema or bronchitis. In this issue of The Journal of Physiology, Taylor-Clark et al. (2008) investigate the role of the transient receptor potential (TRP) channels, TRPV1 and TRPA1, as sensors for oxidative stress in the airways. The heat and capsaicin receptor, TRPV1, has long been thought to play a role in the detection of noxious chemicals in the airway. However, mice lacking the TRPV1 ion channel display only partial defects in nocifensive responses to inhaled irritants (Kollarik & Undem, 2004). Thus, other receptors are required for the detection of irritants by vagal neurons. The ion channel TRPA1 has now emerged as a leading candidate for an airway irritant detector. TRPA1 is highly expressed in a subset of TRPV1-expressing primary sensory afferents and has been shown to play a key role in pain and neurogenic inflammation. TRPA1 is activated by reactive environmental irritants such as mustard oil, cinnemaldehyde and the α,β-unsaturated aldehyde, acrolein, an airway irritant present in tear gas, vehicle exhaust and smoke (Jordt & Ehrlich, 2007). Recent studies have identified a number of reactive endogenous molecules that activate TRPA1 including 4-HNE, 4-HHE and 4-ONE, products of oxidative stress-induced lipid peroxidation (Macpherson et al. 2007; Trevisani et al. 2007; Andersson et al. 2008). Taylor-Clark et al. (2008) use a variety of techniques to examine the role of TRPA1 in the airways. Using calcium imaging they show that cultured vagal neurons innervating the respiratory tract are potently activated by the lipid peroxidation product 4-ONE. At lower concentrations of 4-ONE, calcium responses are absent in neuronal cultures generated from TRPA1-deficient mice. However, at higher concentrations, 4-ONE elicits robust calcium influx in TRPA1-deficient neurons; these responses are attenuated in TRPV1-deficient neurons. These results suggest that both TRPA1 and TRPV1 contribute to cellular sensitivity of lipid peroxidation products. Further analysis of the relative contributions of these channels to 4-ONE sensitivity must await the characterization of neurons from animals lacking both TRPV1 and TRPA1. To address the role of TRPA1 in the airways in situ, Taylor-Clark et al. measure the effects of lipid peroxidation products on contractions of isolated bronchi. They find that 4-ONE induces robust bronchi contraction via sensory neuron-mediated release of neuropeptides. Strikingly, 4-HNE had little effect on bronchi contraction. The authors also use an ex vivo vagally innervated lung preparation to record action potential discharge in response to irritant application. While 4-ONE robustly evoked action potential discharge, 4-HNE had no effect on fibre firing. Responses to 4-ONE were not observed in lung preparations isolated from TRPA1-deficient mice, demonstrating that TRPA1 is required for 4-ONE airway sensitivity. It is surprising that 4-HNE has little effect on bronchi contraction or action potential firing in lung afferents, as this chemical robustly stimulates calcium influx through TRPA1 in cultured sensory neurons and TRPA1-transfected cell lines (MacPherson et al. 2007; Trevisani et al. 2007; Andersson et al. 2008; Taylor-Clark et al. 2008). Also, 4-HNE was shown to elicit robust TRPA1-dependent nocifensive behaviour when injected subcutaneously into the hindpaw of mice (Trevisani et al. 2007). This suggests that TRPA1 sensitivity to irritants may differ depending on the tissue environment. In addition, tissue-specific signalling pathways may differentially modulate sensory neuron excitability in response to ROS. Taken together these findings suggest that TRPA1 activation by 4-ONE is a key mechanism that links oxidative stress to nocifensive responses in the airway. A recent study by Bessac et al. (2008) also probes the role of TRPA1 in airway irritancy. Their study demonstrates that TRPA1 is required for nocifensive airway responses to the reactive oxygen species, hydrogen peroxide. Individuals with altered respiratory function display hypersensitivity to environmental irritants that robustly activate TRPA1. Thus, TRPA1 may represent a new target for the development of drugs that suppress neuronal hypersensitivity in individuals with airway disease.

Dor: aspectos atuais da sensibilização periférica e central

JUSTIFICATIVA E OBJETIVOS: As pesquisas recentes têm focalizado a plasticidade bioquímica e estrutural do sistema nervoso decorrente da lesão tissular. Os mecanismos envolvidos na transição da dor aguda para crônica são complexos e envolvem a interação de sistemas receptores e o fluxo de íons intracelulares, sistemas de segundo mensageiro e novas conexões sinápticas. O objetivo deste artigo foi discutir os novos mecanismos que envolvem a sensibilização periférica e central. CONTEÚDO: A lesão tissular provoca aumento na resposta dos nociceptores, chamada de sensibilização ou facilitação. Esses fenômenos iniciam-se após a liberação local de mediadores inflamatórios e a ativação de células do sistema imune ou de receptores específicos no sistema nervoso periférico e central. CONCLUSÕES: As lesões do tecido e dos neurônios resultam em sensibilização de nociceptores e facilitação da condução nervosa central e periférica.

Eccentric exercise alters muscle sensory motor control through the release of inflammatory mediators

Following downhill exercise, muscle damage and local inflammatory reactions, induced by lengthening contractions, are observed and voluntary muscle activation decreases. The hypothesis that feedback carried by the group IV muscle afferents could be involved has often been raised but never measured in vivo in these conditions. In this experiment, we tested the response of the group IV muscle afferents from the lower limb to injections of KCl and lactic acid in non-exercising rats and at 1, 2, and 8 days after one running session (−13°, 16 m/min). At days 1 and 2, the baseline discharge of the group IV afferents increased, but further activation by test agents was absent. After 8 days, the afferent response was equivalent to the control response. Pretreatment with betamethasone before exercise abolished the effects of downhill exercise. In non-exercising rats, arachidonic acid evoked group IV afferent discharge and suppressed their further response to another stimulus. These results demonstrate that exhaustive downhill running highly activates, for at least 2 days, the sensory feedback carried by group IV afferents through the local release of inflammatory mediators. Such an altered sensori-motor control, accompanying the post-eccentric inflammatory syndrome, could play a key role in deterioration of muscle performance and of its voluntary activation.

The Lip Lipoprotein from Neisseria gonorrhoeae Stimulates Cytokine Release and NF-κB Activation in Epithelial Cells in a Toll-like Receptor 2-dependent Manner

The human pathogen Neisseria gonorrhoeae produces an array of diseases ranging from urethritis to disseminated gonococcal infections. Early events in the establishment of infection involve interactions between N. gonorrhoeae and the mucosal epithelium, which leads to the local release of inflammatory mediators. Because of this, it is important to identify the bacterial virulence factors and host cell components that contribute to inflammation. Using a series of column chromatography steps, we purified a lipoprotein from N. gonorrhoeae strain F62 called Lip. This outer membrane antigen expresses a conserved epitope known as H.8, which is common to all pathogenic Neisseria species. We found the purified preparation of Lip to be a potent inflammatory mediator capable of inducing the release of the chemokine interleukin (IL)-8 and the cytokine IL-6 by immortalized human endocervical epithelial cells and the production of IL-8 and the activation of the transcription factor NF-kappaB by human embryonic kidney 293 (HEK) cells transfected with toll-like receptor (TLR) 2. Upon removal of Lip by immunoprecipitation, the ability of the H.8/Lip preparation to stimulate NF-kappaB activation was abolished. In addition to TLR2, the activation of NF-kappaB by H.8/Lip in HEK cells was enhanced upon coexpression of TLR1 but not TLR6. These observations provide evidence that Lip is capable of inducing the release of inflammatory mediators from epithelial cells in a TLR2-dependent manner.

Measurement of Inflammatory Mediators of Mast Cells and Eosinophils in Native Nasal Lavage Fluid in Nasal Polyposis

Background: Nasal polyposis (NP) often coexists with asthma, rhinitis and sinusitis. Polyp histology typically shows chronic, eosinophilic inflammation. The inflammatory cell infiltrate generally includes eosinophils, lymphocytes, plasma cells and mast cells. Objective: To gain insight into the natural history of NP, we analysed mediator levels and leukocyte values in nasal fluids and eosinophil cationic protein (ECP), total IgE levels and eosinophils in the blood in several groups of both allergic and non-allergic patients with nasal polyps and in patients with allergic rhinitis (AR). Methods: Thirty-two patients with nasal polyps entered the study. As a control group, we studied 55 patients with AR, i.e. 20 patients with seasonal AR to grass pollen, 24 with AR sensitive to Parietaria and 11 with AR sensitive to house dust mite (HDM). Eighteen patients with nasal polyps were also allergic patients (8 were sensitive to Parietaria and 10 were sensitive to HDM), whereas 14 were non-allergic patients. Tryptase and histamine values were assayed in nasal fluids, whereas total IgE was determined in serum. ECP values were assayed both in nasal fluids and serum. Eosinophils were quantified both in the blood and nasal fluids. Results: Tryptase levels were significantly higher in the nasal lavages from patients with NP than in those from patients without NP (4.7 vs. 3.5 U/l, p < 0.001) and correlated with symptom scores (r_s = 0.42, p < 0.0001). The median levels of histamine in nasal fluids from patients with NP were also significantly higher than those observed in patients without NP (50.0 vs. 21.3 ng/ml, p < 0.001), but did not correlate with symptom scores. Finally, the median levels of ECP in nasal fluids from patients with NP were significantly higher than those observed in patients without NP (38.1 vs. 16.1 ng/ml, p < 0.001) and correlated with symptom scores (r_s = 0.38, p < 0.001). Analysis of variance showed that, among the variables studied, the presence of nasal polyps was the factor responsible for the higher levels of tryptase, histamine and ECP in nasal fluids. With regard to leukocyte counts in nasal fluids, no significant differences were observed between rhinitis patients with NP and those without NP. With regard to serum ECP and serum total IgE, no significant differences were detected between the two groups under study. Blood eosinophil levels in patients with NP were significantly higher than those observed in patients without NP (5.8 vs. 5.6, p = 0.002). Analysis of variance showed that both the presence of nasal polyps and the type of sensitisation were important. Considering the total symptom scores, no significant differences were observed between rhinitis patients with NP and those without NP. Conclusions: The present findings are consistent with the view that chronic eosinophil mucosal inflammatory disease in NP involves a self-sustaining mechanism, i.e. local release of inflammatory mediators, independent of allergen stimulation of nasal mucosa. Increased release of inflammatory mediators contributes to the development of nasal polyps, determining oedema and an increased recruitment of inflammatory cells. Besides eosinophils, mast cells also play a key role in this process.

Systemic inflammatory response syndrome

Systemic inflammatory response syndrome is a term used to describe the host's response to infection or diffuse tissue injury characterized by the release of various proinflammatory and antiinflammatory mediators. The local release of inflammatory mediators is critical in the development of a systemic inflammatory response. If the initial response is balanced and contained, homeostasis is preserved. However, if either response is excessive, systemic involvement and end organ damage occur. Understanding the relationships between the initiators and secondary mediators generated in response to inflammation improves our understanding of the clinical syndrome associated with infection and progressive multiple system organ dysfunction. It also creates a potential role for the use of cytokines in early diagnosis of infection and development of targeted therapeutic strategies to attenuate the systemic inflammatory response and improve clinical outcome. Copyright © 2001 by W.B. Saunders Company

Influence of oxygen supply on activation of group IV muscle afferents after low-frequency muscle stimulation.

Anaerobic muscle metabolism and local release of inflammatory mediators play key roles in the mechanism of postfatigue-induced activation of group IV muscle afferents. The present study focused on activation of these muscle afferents after a 3-min period of low-frequency muscle stimulation (LFMS) in different conditions of muscle oxygenation, such as occur in patients with respiratory insufficiency and subjects living at high altitude. In anesthetized rabbits, spontaneous activity of group IV afferents (conduction velocity = 1.52 +/- 0.13 m.s(-1)) from the tibialis anterior muscle was recorded at rest (baseline) and then after LFMS under normoxic (PaO(2) = 113 mmHg), hyperoxic (PaO(2) = 186 mmHg), or hypoxic (PaO(2) = 35 mmHg) conditions. The maximal force decay at the end of LFMS did not differ significantly with respect to conditions of muscle oxygenation. Compared with normoxia, hypoxia significantly increased the baseline activity of group IV muscle afferents, whereas no effect was noted when hypoxia followed a period of hyperoxia. LFMS-induced activation of group IV afferents occurred in all circumstances, except when hypoxia was first tested. The activation of group IV muscle afferents after LFMS was markedly reduced when hypoxia followed normoxia (+14% versus +27%) or hyperoxia (+55% versus +144%), whereas it was accentuated when hyperoxia followed hypoxia (+25% versus +8%). We concluded that the sensorimotor control of skeletal muscles may be altered during acute hypoxia but facilitated after reoxygenation.

Nasal polyposis: Immunohistochemistry and bioelectrical findings (a hypothesis for the development of nasal polyps)

Nasal polyps and turbinates were obtained from individuals undergoing surgery for symptomatic nasal obstruction caused by nonatopic rhinosinusitis or allergic rhinosinusitis. One part of the tissue from each patient was fixed in neutral buffered formalin and prepared for study by histochemical and immunohistochemical methods. Monoclonal antibodies were used to identify macrophages, lymphocytes, and plasma cells. In most cases (12 of 16, 75%) the remainder of the polyp and turbinate samples was treated with protease to achieve disaggregation of the epithelial cells. Those cells were cultured on permeable collagen matrix supports. Transepithelial potential difference and resistance were measured daily. At the time of maximal transepithelial potential difference, the epithelial cells were mounted in modified Ussing chambers and exposed to a sodium-positive channel blocker (amiloride hydrochloride) and to selected chloride-negative channel agonists (isoproterenol bitartrate and adenosine triphosphate). Middle turbinates and polyps were found to have more macrophages, lymphocytes, plasma cells, HLA-DR–positive cells, and eosinophils than the inferior turbinates. Epithelial cells obtained from polyps exhibited higher transepithelial potential differences and equivalent short-circuit currents than turbinate cell cultures. The responses to amiloride, isoproterenol, and adenosine triphosphate were also greater for polyp than for turbinate cultures. A theory for the pathogenesis of nasal polyps is proposed. Local release of inflammatory mediators could cause sodium absorption and chloride permeability to be higher in polyps than in turbinate epithelia. Increased sodium absorption is consistent with the hypothesis that epithelial fluid absorption contributes to the development of nasal polyps and is a result of the increased recruitment of inflammatory cells, which are present in nasal polyps. (J Allergy Clin Immunol 1997;99:165-75.)

Macrophage phagocytosis of myelin in vitro determined by flow cytometry: phagocytosis is mediated by CR3 and induces production of tumor necrosis factor- α and nitric oxide

Demyelination of axons in the central nervous system (CNS) during multiple sclerosis (MS) and its animal model experimental allergic encephalomyelitis (EAE) is a result of phagocytosis and digestion by macrophages (M ϕ) and the local release of inflammatory mediators like tumor necrosis factor- α (TNF- α) and nitric oxide (NO). We have investigated the process of myelin phagocytosis by M ϕ in vitro using flow cytometric analysis. The binding and uptake of CNS-derived myelin was dose dependent, was abolished in the presence of EDTA and was enhanced after opsonization with complement. The phagocytosis of opsonized myelin could be inhibited by antibodies directed against complement receptor type 3 (CR3). Furthermore, CR3 also contributes to phagocytosis of non-opsonized myelin, e.g. under serum-free conditions. The phagocytosis of CNS-derived myelin induced the production of substantial amounts of TNF- α and NO by the M ϕ. Our results indicate an important role for CR3 in myelin phagocytosis. The induction of TNF- α and NO which accompanies this phagocytosis may further contribute to the overall process of demyelination during MS or EAE.

Tumor Necrosis Factor and IL‐1β Expression in Pediatric Patients with Inflammatory Bowel Disease

SummaryThe local release of inflammatory mediators are intricately linked with initiation and propagation of the inflammatory reaction in ulcerative colitis (UC) and Crohn's disease. We have used immunohistochemical staining of colonic biopsies to determine the cell of origin and the location of the cells which synthesize of TNF‐α and IL‐1β in patients with UC and Crohn's colitis. Patients were chosen from children aged 7–16 years, who had UC or Crohn's diagnosed following review of colonic biopsies taken during colonoscopy. The patients reviewed had not received treatment for inflammatory bowel disease. Paraffin embedded colonic biopsies were sectioned, deparaffinized, and stained with mouse monoclonal IgG antibodies directed against human recombinant TNF‐α and IL‐1β. The colonic lamina propria of all biopsies from patients with UC or Crohn's colitis was expanded with a mixed mononuclear, polymorphonuclear, lymphocytic, and plasmacytic infiltrate. Mononuclear cells distributed throughout the interstitium, stained prominently for both TNF‐α and IL‐1β. Plasmacytes, polymorphonuclear leukocytes, small lymphocytes, and foamy macrophages did not stain for either TNF‐α or IL‐1β. Transmigrating mononuclear cells in crypt epithelium also stained brightly for both TNF‐α and IL‐1β. Colonic epithelial cells did not stain for either TNF‐α or IL‐1β. We conclude that (a) expression of both TNF‐α and IL‐1β is significantly increased in colonic biopsies from patients with both UC and Crohn's colitis, (b) mononuclear cells appeared to be the primary source for TNF‐α and IL‐1β in patients with UC and Crohn's colitis, and (c) mononuclear cells synthesizing TNF‐α or IL‐1β are distributed throughout both the intestinal crypts and interstitium.

Tumor necrosis factor and IL-1 beta expression in pediatric patients with inflammatory bowel disease.

The local release of inflammatory mediators are intricately linked with initiation and propagation of the inflammatory reaction in ulcerative colitis (UC) and Crohn's disease. We have used immunohistochemical staining of colonic biopsies to determine the cell of origin and the location of the cells which synthesize of TNF-alpha and IL-1 beta in patients with UC and Crohn's colitis. Patients were chosen from children aged 7-16 years, who had UC or Crohn's diagnosed following review of colonic biopsies taken during colonoscopy. The patients reviewed had not received treatment for inflammatory bowel disease. Paraffin embedded colonic biopsies were sectioned, deparaffinized, and stained with mouse monoclonal IgG antibodies directed against human recombinant TNF-alpha and IL-1 beta. The colonic lamina propria of all biopsies from patients with UC or Crohn's colitis was expanded with a mixed mononuclear, polymorphonuclear, lymphocytic, and plasmacytic infiltrate. Mononuclear cells distributed throughout the interstitium, stained prominently for both TNF-alpha and IL-1 beta. Plasmacytes, polymorphonuclear leukocytes, small lymphocytes, and foamy macrophages did not stain for either TNF-alpha or IL-1 beta. Transmigrating mononuclear cells in crypt epithelium also stained brightly for both TNF-alpha and IL-1 beta. Colonic epithelial cells did not stain for either TNF-alpha or IL-1 beta.(ABSTRACT TRUNCATED AT 250 WORDS)