Induction of tumor necrosis factor-alpha and apoptosis in gastric mucosal injury by indomethacin: effect of omeprazole and ebrotidine

BACKGROUND: Inhalation of swine dust causes airway inflammation with influx of inflammatory cells, predominantly neutrophils, into the lungs. A study was undertaken to determine whether or not exposure to swine dust induces release of interleukin 8 (IL-8) into upper and lower airways and how this possible release is related to cellular influx. A further aim was to study the relationship between the inflammatory response and swine dust exposure. METHODS: Thirty one healthy, non-smoking, previously unexposed subjects were exposed to swine dust during three hours work in a swine house. Bronchoalveolar lavage (BAL) was performed two weeks before and 24 hours after the exposure (n = 16). Nasal lavage and acoustic rhinometry were carried out 1-2 hours before and seven hours after the start of the exposure (n = 31). Exposure measurements were performed with personal sampling equipment. RESULTS: The exposure led to 19-fold and 70-fold increases in the neutrophil concentrations in nasal lavage and BAL fluid, respectively (p < 0.001). In BAL, fluid macrophages, lymphocytes and eosinophils increased significantly. The IL-8 levels in BAL fluid increased from < 31.3 ng/l to 63 (43-109) ng/l (median (25-75th percentile), p < 0.001), and in nasal lavage fluid the concentrations increased from 144 (97-227) ng/l to 1064 (864-1437) ng/l (p < 0.001). IL-8 levels showed a significant correlation with the increase in neutrophils in the nasal lavage fluid but not in the BAL fluid. Acoustic rhinometry demonstrated significant swelling of the nasal mucosa. The air concentration of inhalable dust was 23.3 (20.0-29.3) mg/m3, endotoxin 1.3 (1.1-1.4) micrograms/m3, and muramic acid 0.99 (0.78-2.1) microgram/m3. CONCLUSIONS: The concentration of IL-8 increases in BAL fluid and nasal lavage fluid following exposure to swine dust and may be one of the chemoattractants contributing to the recruitment of neutrophils to the nasal cavity and the alveolar space.     

Elevated levels of IL-6, INF-gamma, and TNF-alpha in mice in response to cotton dust are modulated by anti-TNF-alpha antiserum

Acute pulmonary neutrophilic inflammation triggered by cotton dust exposure is one of the features of organic dust syndrome. Studies with a mouse model have reproduced the inflammation and have shown the presence of tumor necrosis factor-alpha (TNF-alpha) in the bronchoalveolar lavage (BAL) fluid of mice following a 3-h exposure to respirable cotton dust particles. A cover glass technique for cytospin samples of BAL cells resulted in a 42-fold increase in cell count, with 76% neutrophils, 13% lymphocytes, and 10% macrophages, after cotton dust exposure. Immunohistochemical staining of lung specimens with anti-TNF-alpha antiserum revealed TNF in the cells surrounding pulmonary airways and vessels. Cotton dust exposure resulted in elevated TNF-alpha, IL-6, and INF-gamma in BAL fluid, INF-gamma and IL-6 in serum. Administration of anti-TNF-alpha antiserum prior to the organic dust exposure resulted in a marked attenuation of the pulmonary inflammatory cell response, as well as decreased IL-6 and TNF-alpha levels in BAL fluid and decreased IL-6 and INF-gamma in serum. These results indicate TNF modulation of the dust-induced toxic alveolitis and cytokine production.     

Serial prognostic capabilities of electrocardiographic indices of infarcted and hibernating myocardium in predicting short- and long-term outcome following coronary artery bypass surgery

Concentrations and ex vivo production of interleukin 1 beta (IL-1), tumour necrosis alpha (TNF), interleukin 6 (IL-6), interleukin-1 receptor antagonist (IL-1RA) and TNF soluble receptors (sTNF-receptors, P55 and P75) were measured in bronchoalveolar lavage (BAL) fluid and blood in 23 HIV-seropositive (HIV+) patients with Pneumocystis carinii pneumonia (PCP) and compared with values found in healthy HIV-seronegative (HIV-) controls and asymptomatic HIV+ subjects. Concentrations of the proinflammatory cytokine IL-1 beta were increased in BAL fluid of HIV+ patients with PCP (184 +/- 47 pg mL-1) compared with undetectable levels in healthy control subjects (P = 0.0001). In plasma of these patients higher concentrations of the anti-inflammatory cytokine IL-1RA were found during acute PCP than after recovery (2.1 +/- 0.7 vs. 0.5 +/- 0.2 ng mL-1, P = 0.01). No correlations could be found between cytokine concentrations and clinical severity of the infection. Corticosteroid treatment did not influence cytokine concentrations in BAL or blood, nor did it suppress the production in alveolar cells. In whole-blood cultures, however, lipopolysaccharide (LPS)-stimulated production was significantly suppressed for IL-1 (1.3 vs. 5.5 ng mL-1, P = 0.009) and for IL-6 (0.6 vs. 2.5 ng mL-1, P = 0.01). The overall data show that in HIV+ patients with PCP (similar to what we had found previously in HIV-patients with PCP) proinflammatory cytokines are more prominently present in BAL, whereas anti-inflammatory reaction is predominant in the circulation.     

Monocyte cytokine production in an elderly population: effect of age and inflammation

OBJECTIVE: To determine the association among aging, inflammation, and cytokine production by peripheral blood mononuclear cells. POPULATION AND METHODS: We examined production of interleukin-1 beta (IL-1 beta), tumor necrosis factor-alpha (TNF-alpha), IL-1 receptor antagonist (IL-1Ra), and IL-6 in 711 elderly participants in the Framingham Heart Study (mean age, 79 y) and 21 young healthy volunteers (mean age, 39 y). The elderly subjects were categorized by serum C-reactive protein (CRP) concentration, a marker of systemic inflammation. RESULTS: Production of IL-6 (p < .00001) and IL-1Ra (p < .00001) was higher in the elderly subjects than in the control group. IL-6 production increased with increasing CRP, whereas IL-1RA was uniformly elevated in elderly subjects regardless of CRP. However, we found no difference in the production of IL-1 beta or TNF-alpha between the young and elderly groups, regardless of CRP status. IL-6 population correlated with IL-1 beta (r = .36, p < .0001) and TNF-alpha production (r = .25, p < .0001), but IL-1Ra production did not. CONCLUSION: Production of IL-6 and IL-1Ra--but not IL-1 beta or TNF-alpha--was increased in the elderly compared to healthy, young subjects. The increase in IL-6 also correlated with increased production of CRP, a marker of inflammation. However, IL-1Ra was increased in the elderly independently of CRP production. Although limited by the small control group, these data suggest that dysregulation of some inflammatory cytokines occurs with age, but the role of inflammation in aging remains unclear.     

Interleukin 8 and monocyte chemoattractant protein-1 in patients with juvenile rheumatoid arthritis. Relation to onset types, disease activity, and synovial fluid leukocytes

OBJECTIVE: To measure serum and synovial fluid (SF) levels of interleukin 8 (IL-8) and monocyte chemoattractant protein-1 (MCP-1) in patients with juvenile rheumatoid arthritis (JRA) and to compare them with adult rheumatoid factor-positive rheumatoid arthritis (RA). METHODS: IL-8 and MCP-1 were measured by immunoassay (1) in sera obtained from 55 children with JRA and from 16 adults with RA, and (2) in SF obtained from 30 children with JRA and 11 adults with RA. RESULTS: Patients with active systemic JRA had serum levels of IL-8 and MCP-1 higher than in controls (p<0.01) and in patients with active polyarticular or pauciarticular JRA (p<0.05). In patients with RA serum MCP-1 levels were higher than in patients with the 3 JRA onset types, while no difference was found for IL-8 levels. Patients with systemic JRA and with current systemic features had serum levels of IL-8 and MCP-1 higher (p = 0.03 and p = 0.04, respectively) than patients in which systemic features had subsided. No significant differences in SF IL-8 or MCP-1 levels were found among the 3 JRA onset types or adults with RA. In patients with JRA SF leukocyte counts were correlated with SF IL-8 levels (p = 0.002), but not with MCP-1 levels. Moreover, SF levels of both IL-8 and MCP-1 were correlated with those of IL-1beta (p<0.001) and IL-6 (p<0.01), but not with those of TNF-alpha. CONCLUSION: Elevated serum levels of IL-8 and MCP-1 in patients with systemic JRA with current systemic features at sampling suggest systemic production of the 2 chemokines during systemic phases of the disease. Similar SF levels of IL-8 and MCP-1 among the 3 JRA onset-types and RA suggest comparable local production of the 2 chemokines.     

Clinical utility of CA125 levels in predicting laparoscopically confirmed salpingitis in patients with clinically diagnosed pelvic inflammatory disease

To investigate immune system function in obsessive-compulsive disorder (OCD) we measured plasma levels of tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta) and interleukin-6 (IL-6) in 14 drug-free obsessive-compulsive patients and 14 matched healthy controls. No significant differences were observed between patients and controls in plasma levels of IL-1 beta and IL-6, whereas plasma levels of TNF-alpha were significantly lower (p = 0.001) in the former. Blood levels of prolactin did not differ between the two groups, whereas plasma cortisol concentrations were significantly higher in patients than in healthy subjects (p = 0.02). No significant correlation was found between immune parameters, on the one hand, and endocrine or psychopathological measures on the other. These results suggest that OCD is associated with a decreased production in TNF-alpha, but normal synthesis of IL-1 beta and IL-6.     

Identification of two closely related genes, inducible and noninducible carbonyl reductases in the rat ovary

OBJECTIVE: To investigate the potential role of cytokines in psoriatic arthritis (PsA) by assessing the profiles of the proinflammatory cytokines in synovial fluid (SF) of PsA in comparison with rheumatoid arthritis (RA) and osteoarthritis (OA). METHODS: Levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 1 (IL-1), IL-6, and IL-8 were measured in SF using ELISA. RESULTS: Levels of TNF-alpha, IL-1beta, and IL-8 were significantly higher in PsA SF than in OA SF, although lower than in RA SF. No difference was detected in the IL-6 levels between PsA and RA SF, both of which were much higher than in OA SF. CONCLUSION: The pattern of expression of proinflammatory cytokines seen in PsA is similar to that in RA. Since PsA is also a destructive arthropathy, cytokines, in particular TNF-alpha and IL-1, may be principle factors in joint destruction.     

Cytokine and eosinophil responses in the lung, peripheral blood, and bone marrow compartments in a murine model of allergen-induced airways inflammation

Selective accumulation of eosinophils and activated CD4+ cells is now considered a central event in the pathogenesis of asthma, and this process is thought to be mediated by a number of cytokines including tumor necrosis factor-alpha (TNF-alpha), granulocyte-macrophage colony-stimulating factor (GM-CSF), and the Type 2 cytokines interleukin-4 (IL-4) and IL-5. To carry out a detailed time-course analysis of cellular changes in the bronchoalveolar lavage fluid (BAL), peripheral blood (PB), and bone marrow (BM), and of changes in the aforementioned cytokines in BAL and serum, Balb/c mice were sensitized by intraperitoneal injection with ovalbumin (OVA) adsorbed to aluminum hydroxide on two occasions 5 days apart, and were subjected to an OVA aerosol challenge 12 days after the second sensitization. This resulted in an airways inflammatory response characterized by early transient neutrophilia, marked eosinophilia, and, to a lesser extent, lymphocytosis in the BAL. Inflammatory events were first observed 3 h and 24 h after antigen challenge in the lung tissue and BAL, respectively, and lasted for 21 days. In the BM, we detected a 1.5- and 5-fold increase in the total number of cells and eosinophils, respectively, 4 days after the second sensitization. This was followed by a decrease, although BM eosinophilia remained clearly present at the time of antigen challenge. A second eosinopoietic event was observed in the BM shortly after challenge and reached a peak at day 3. BM cellularity returned to normal at day 21 after challenge. Serum OVA-specific IgE was first detected 3 days following the second sensitization (150 ng/ml). IgE levels then decreased but remained at the 75 ng/ml range at the time of the aerosol challenge. During the sensitization period, TNF-alpha (approximately 25 pg/ml), IL-4 (approximately 40 pg/ml), and IL-5 (approximately 250 pg/ml) were detected in serum, but not in the BAL fluid (BALF) and returned to background levels at the time of the antigen challenge. After antigen challenge, TNF-alpha, IL-4, IL-5, and GM-CSF were detected in serum. Peak levels were observed at 3 h (approximately 40 pg/ml), 3 h (approximately 120 pg/ml), 12 h (approximately 350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, and returned to background levels 24 h after challenge. In the BALF, we detected peak levels of TNF-alpha, IL-4, IL-5, and GM-CSF at 6 h (approximately 250 pg/ml), 24 h (approximately 140 pg/ml), 24 h (350 pg/ml), and 3 h (approximately 10 pg/ml), respectively, with a return to background levels 5 days after challenge. No IL-10 could be detected at any time point during sensitization or after challenge in either serum or BAL. We also detected approximately 40 pg/ml of interferon-gamma (IFN-gamma) in the serum of normal untreated mice. Serum IFN-gamma levels fluctuated during sensitization and after challenge, but never exceeded those observed in untreated mice. Thus, the cytokine profile observed in this experimental model of allergic inflammation is characterized by IL-4 and IL-5 dominance, with an apparently minor TNF-alpha and GM-CSF contribution and relatively low or undetectable levels of IFN-gamma and IL-10.     

TRFK-5 reverses established airway eosinophilia but not established hyperresponsiveness in a murine model of chronic asthma

We studied the effects of an anti-interleukin (IL)-5 monoclonal antibody (TRFK-5) or dexamethasone (DEX) to reverse already established airway hyperresponsiveness (AHR) and tissue eosinophilia in a Schistosoma mansoni antigen-sensitized and airway-challenged mouse model of chronic asthma. In this model at 4 d after antigen challenge there is dramatic bronchoalveolar lavage fluid (BAL) eosinophilia, AHR to intravenous methacholine (MCh), and histologic evidence of peribronchial eosinophilic infiltration and mucoid cell hyperplasia. These changes persist for up to 2 wk after antigen challenge. Treatment with DEX from Days 4 through 10 significantly reduced established airway eosinophilia compared with animals sham-treated with saline from Days 4 -10 (120 +/- 29 eosinophils/microl BAL for DEX-treated mice versus 382 +/- 60 eosinophils/microl BAL for sham-treated animals, p < 0.01). DEX-treated mice also had dramatically reduced mucoid cell hyperplasia, and airway responsiveness returned to normal. In contrast, TRFK-5 given during the same time period reduced airway eosinophilia (86 +/- 32 eosinophils/microl BAL versus 382 +/- 60 eosinophils/microl BAL, p < 0.01) but did not reduce goblet cell hyperplasia or reverse already established AHR. Treatment with DEX but not TRFK-5 also inhibited interferon gamma (IFN-gamma) content of BAL fluid (0.49 +/- 0.09 ng/ml BAL fluid for DEX versus 1.50 +/- 0.24 ng/ml BAL fluid and 1.36 +/- 0.13 ng/ml BAL fluid for TRFK-5 and sham-treated mice, respectively, both p < 0.001 versus DEX). Thus, treatment with DEX reduces established eosinophilic airway inflammation and AHR in S. mansoni-sensitized and airway-challenged mice but treatment with TRFK-5 reversed established eosinophilia without ameliorating established AHR. Together, these data suggest that once airway inflammation develops, neutralizing the effects of IL-5 or reducing eosinophilia alone may not result in inhibiting established AHR in atopic asthma.     

Selective inhibition of hepatic collagen accumulation in experimental liver fibrosis in rats by a new prolyl 4-hydroxylase inhibitor

In order to detect and characterize allergen-specific T cells in the airways of atopic asthmatics, we measured proliferation and cytokine production by bronchoalveolar lavage (BAL) T cells isolated from Dermatophagoides pteronyssinus (Der p)-sensitive asthmatics and nonatopic control subjects, and compared the results with those generated using peripheral blood (PB) T cells. BAL and PB mononuclear cells were collected 24 h after segmental allergen challenge by fibreoptic bronchoscopy and venepuncture, respectively. T cells purified from BAL and PB were stimulated with autologous, irradiated antigen-presenting cells and D. pteronyssinus extract or a control, nonallergen antigen (M. tuberculosis purified protein derivative [PPD]). IL-5 and IFN-gamma concentrations were measured in culture supernatants by ELISA, and T-cell proliferation by 3H-thymidine uptake. D. pteronyssinus-induced proliferation of T cells derived from both BAL and PB was elevated in asthmatics when compared with control subjects (p < 0.05), whereas PPD-induced proliferation was equivalent in both compartments. In the asthmatics, D. pteronyssinus-induced proliferative responses of equivalent numbers of BAL and PB T cells obtained after allergen challenge were statistically equivalent. Nevertheless, BAL T cells stimulated with D. pteronyssinus produced significantly greater amounts of IL-5 than did PB T cells (p < 0.05). Allergen-induced proliferation and IL-5 production by BAL T cells in the asthmatics after segmental allergen challenge correlated with the percentages of eosinophils in the BAL fluid (p < 0.01). Further, BAL T cells from asthmatic patients produced significantly higher amounts of IL-5 than did the same number of cells from nonatopic control subjects (p < 0.05). We conclude that, in D. pteronyssinus-sensitive asthmatics, allergen-specific T cells can be detected in the bronchial lumen after allergen challenge and that allergen-induced proliferation and IL-5 production by these cells correlates with local eosinophil influx. Although bronchial luminal T cells show an equivalent proliferative response to allergen stimulation as compared with PB T cells, they do produce more IL-5, consistent with the hypothesis that local differentiation or priming of these cells within the bronchial mucosal environment results in upregulation of allergen-induced IL-5 secretion.     

Making the most of aid

The synovial fluid (SF) of rheumatoid arthritis (RA) patients contains a mixture of inflammatory mediators. In order to determine whether certain cytokine patterns locally in the joint are specifically related to the chronic inflammation in RA, the concentrations of interleukin (IL)-1alpha, IL-1beta, IL-6, IL-10, transforming growth factor-beta (TGF-beta), tumour necrosis factor-alpha (TNF-alpha) and IgG2b-inducing factor (IgG2bIF) were measured in SF from 22 patients with RA and 22 patients with other types of arthritic lesions. High levels of IL-10, latent and active TGF-beta and the presence of IgG2bIF are significantly correlated with RA when corrected for age. As these factors have the capacity to promote antibody production, they might contribute to the maintenance of local antibody production in RA synovial tissues. All RA-SF samples contained detectable levels of IL-10 and all except one contained IL-1beta, while concentrations in several non-RA-SF samples were below detection limits. IL-6 and TGF-beta were present in all SF samples from both RA and non-RA patients. The presence of IgG2bIF was strongly correlated with high levels of IL-10 and IL-1beta in SF. However, no distinct cytokine profile specific for the chronic inflammation characteristic of RA was found.     

Cytokines in bronchoalveolar lavage fluid in patients with high altitude pulmonary oedema at moderate altitude in Japan

BACKGROUND: The precise mechanism of high altitude pulmonary oedema (HAPE) remains unclear. The purpose of this study was to evaluate the role of cytokines and P-selectin in the development of HAPE which occurred at moderate altitude in Japan. METHODS: The following cellular and biochemical markers and chemotactic cytokines were measured in the bronchoalveolar (BAL) fluid from four patients with HAPE at 2857-3180 m in the Japanese Alps: total proteins, albumin, lactate dehydrogenase (LDH), and interleukin (IL)-1 alpha, IL-1 beta, IL-1 receptor antagonist (ra), IL-6, IL-8, IL-10, tumour necrosis factor (TNF)-alpha, and the soluble form of P-selectin. RESULTS: At admission there were significant increases in the levels of total cells, especially macrophages and neutrophils, total protein, albumin and LDH when compared with 13 healthy individuals. Furthermore, the levels of IL-1 beta, IL-6, IL-8, and TNF-alpha were also considerably increased but returned quickly to the normal ranges or were not detected after recovery. The levels of IL-1 alpha, IL-10, and P-selectin did not change. CONCLUSIONS: These results suggest that an inflammatory process almost identical with acute respiratory distress syndrome (ARDS) may occur in HAPE, but that these changes are transient and are not associated with any increase in P-selectin levels in the BAL fluid.     

Cytokine response in cerebrospinal fluid after birth asphyxia

Experimental studies suggest that cytokine-mediated inflammatory reactions are important in the cascade leading to hypoxic-ischemic brain injury. The purpose was to study the content of pro- and antiinflammatory cytokines in cerebrospinal fluid (CSF) of asphyxiated and control infants. Samples of CSF were obtained from 20 infants who fulfilled the criteria of birth asphyxia and from seven newborn control subjects. The concentrations of IL-1beta, IL-8, IL-10, tumor necrosis factor (TNF)-alpha, and granulocyte/monocyte colony-stimulating factor (GM-CSF) were determined with ELISA and of IL-6 using a bioassay. The concentration of IL-6 (pg/mL) was higher in asphyxiated (250, 35-543; median, interquartile range) than in control (0, 0-18) infants (p = 0.001). There was also a significant relationship between IL-6 and the degree of HIE, and between IL-6 and outcome. In addition, the content of IL-8 (pg/mL) was higher (p = 0.009) in the asphyxia group (170, 70-1440), than in the the control group (10, 0-30) and there was an association between IL-8 and degree of HIE. The levels of IL-10, TNF-alpha, GM-CSF, and IL-1beta did not differ between groups. In conclusion, the proinflammatory cytokines IL-6 and IL-8 were markedly elevated in CSF of asphyxiated infants, and the intrathecal levels of these cytokines corresponded to the degree of HIE.     

Purification and characterization of aminopeptidase P from Lactococcus lactis subsp. cremoris

BACKGROUND: Neutrophils, platelets, and cytokines are thought to play a pivotal role in the pathogenesis of endotoxin-induced lung injury which resembles features of acute respiratory distress syndrome (ARDS). For initiation of this pathological process, neutrophils and platelets are activated and adhere to pulmonary endothelium. Nitric oxide (NO) inhibits adhesion and activation of these cells and decreases the cytokine level in bronchoalveolar lavage (BAL) fluid obtained from patients with ARDS. Limited data are available on the effect of NO treatment before and after endotoxin on the development and advance of ARDS. The aim of the current study was to determine whether NO inhalation prevents acute lung injury. METHODS: Thirty-two male anaesthetized rabbits were randomly assigned to receive one of four treatments (n = 8 each); Group S-N received saline with nitrogen (N2), Group S-NO received saline infusion with NO (20 p.p.m.) inhalation, Group E-N received an infusion of Escherichia coli endotoxin 100 micrograms/ kg over 60 min with inhalation of N2, and Group E-NO received endotoxin with NO (20 p.p.m.) inhalation. The lungs of the rabbits were ventilated with 40% oxygen until 6 h after the start of endotoxin or saline administration. Haemodynamics and PaO2 were recorded during the ventilation period. After observation, the lung wet-to dry-(W/D) weight ratio, lung mechanics, and cell fraction, activated complements, cytokines, arachidonic acid metabolites, and albumin concentrations in the BAL fluid were measured and analysed. Light microscopic findings were compared among the four groups. RESULTS: Pulmonary hypertension and deterioration of oxygenation by endotoxin were less pronounced in rabbits receiving NO. The lung compliance after endotoxin was similar in Groups E-NO and E-N. The W/D weight ratio and neutrophils and albumin concentrations in the BAL fluid increased in Groups E-NO and E-N. The BAL fluid concentrations of interleukin-8, thromboxane A2, and prostacyclin were similar in the two endotoxin-treated groups. Endotoxin caused extensive morphologic lung damage regardless of NO inhalation. CONCLUSIONS: The increase in pulmonary arterial pressure and deterioration of oxygenation were less in endotoxin-exposed rabbits receiving NO inhalation compared with those receiving N2. Accumulation of neutrophils and platelets in the lung, morphological lung damage, and the release of cytokines and prostanoids were observed in the E-NO group. However, we are unable to extrapolate these results directly to the human clinical setting because of the short observation period, the use of only one dose of NO, and the species difference.     

Isolation of bioactive compounds from Helix aspersa nerve tissue and the effect of pQPPLPRYamide on heart, esophagus and central neurons of H. aspersa and rectum of Anodonta woodiana

1. Tumour necrosis factor-alpha (TNF-alpha) is implicated in the pathogenesis of many pulmonary and airway diseases. TNF-alpha stimulation may release interleukin-8 (IL-8) in airways mediated via an increase in intracellular oxidant stress. In the present study, we have assessed leukosequestration and IL-8 release in the airways in response to intratracheal administration of human recombinant TNF-alpha, and examined the modulatory role of endogenous NO by pretreatment with a NO synthase inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME). 2. TNF-alpha (10(2)-10(-4) u) was administered intratracheally in male guinea-pigs which were anaesthetized with urethane and were ventilated artificially. TNF-alpha induced a time- and dose-related increase in neutrophil numbers and a concomitant increase in human IL-8 equivalent level retrieved from bronchoalveolar lavage (BAL) with the peak effect at 10(3) u at 6 h of TNF-alpha injection (late phase). Intratracheal administration of recombinant human (rh)IL-8 (0.025, 0.25, 2.5 ng) producing a similar range of human IL-8 equivalent levels in BAL as measured in our results induced neutrophil recovery in BAL fluid to a similar extent. Administration of anti-IL-8 antibody prevented the late phase of neutrophil recruitment induced by TNF-alpha or rhIL-8. 3. Pretreatment with L-NAME significantly enhanced the TNF-alpha (10(3) u)-induced neutrophil recruitment and human IL-8 equivalents production at 6 h, but not at 1 h of TNF-alpha administration (early phase). L-Arginine reversed the responses to L-NAME. Pretreatment with 0.2% DMSO (i.v.) significantly inhibited TNF-alpha-induced neutrophil recruitment and human IL-8 equivalents release both in the early and late phase of the responses. Pretreatment with DMSO also inhibited the enhancement effect of L-NAME on the late phase of TNF-alpha-induced responses. DMSO failed to modify exogenous rhIL-8-induced neutrophil recruitment. Neither L-NAME nor DMSO alone induced any significant change in neutrophil numbers or human IL-8 equivalent level in BAL fluid. 4. Neutrophil depletion by cyclophosphamide pretreatment failed to modify TNF-alpha-induced human IL-8 equivalent release. 5. The expression of beta 2-integrin, CD11b/CD18 on neutrophils was increased only in the late but not early phase of TNF-alpha stimulation. L-NAME failed to modify these responses. 6. In conclusion, we demonstrated that NO may be an important endogenous inhibitor of TNF-alpha-induced leukocyte chemotaxis via inhibition of IL-8 production. Thus, the production of NO in airway inflammatory diseases may play a negative feedback role in self-limiting the magnitude of inflammatory responses.     

The roles of cytokines and retinoic acid in the regulation of human thyroid cancer cell growth

The purpose of this study was to investigate the effects of cytokines and retinoic acid in human thyroid cancer cell growth. Cellular proliferation studies of the CGTH W-1 and SW 579 cell lines were performed with various cytokines and all-trans retinoic acid (RA). Cell number was determined by cell counting and incorporation of [3H]thymidine into DNA. Inhibitory effects of tumour necrosis factor alpha (TNF-alpha) were found in both cell lines. SW 579 was more sensitive to TNF-alpha. The SW 579 cell line revealed gradually decreased cell proliferation in [3H]thymidine incorporation studies as TNF-alpha concentration increased. In contrast, the CGTH W-1 cell line revealed prominent suppressive effects when the TNF-alpha concentrations increased over 1 ng/ml. An inhibitory effect of interleukin 1 beta (IL-1 beta) on CGTH W-1 cells was noted at the concentration of 1 ng/ml, however, IL-1 beta failed to demonstrate an inhibitory effect in SW 579 cells.     

Distribution of asbestos bodies in the human lung as determined by bronchoalveolar lavage

Asbestos-related lung diseases tend to have distinct local distributions, for example, asbestosis first appears and tends to be more severe in the peripheral parts of the lower lung zones. The risk for asbestosis is related to the total asbestos burden of the lung. This suggests that the lower lobes in asbestos-exposed individuals may contain more asbestos than the other lobes. To test whether such topographic differences exist, we compared the number of retrieved asbestos bodies (AB) per ml BAL fluid in three groups of occupationally asbestos-exposed subjects who underwent BAL at different sampling sites. In Group 1 (n = 24) we performed BAL at three sites, namely in a segment of the right upper, right middle, and right lower lobe, to evaluate differences in asbestos body burden from lung apex to basis. There was a distinct increase in BAL asbestos body concentrations from the upper (21.2 +/- 9.1 AB/ml BAL fluid) to the middle (30.4 +/- 12.8 AB/ml BAL fluid) and to the lower lobe (56.0 +/- 20.2 AB/ml BAL fluid), all differences being significant (p < 0.01). In Group 2 (n = 40), we found good interlobar correlations for asbestos body counts between the right middle lobe (21.0 +/- 5.8 AB/ml BAL fluid) and the lingula (22.4 +/- 5.9 AB/ml BAL fluid) (r = 0.941, p < 0.001) and, in Group 3 (n = 15), between the ventral basal segment of the right (41.2 +/- 13.6 AB/ml BAL fluid) and left lung (39.0 +/- 13.6 AB/ml BAL fluid) (r = 0.966, p < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)