Plasma-derived proteins in airway defence, disease and repair of epithelial injury

One significant characteristic of the airway mucosa in vivo, that cannot easily be mimicked in vitro, is its microcirculation, which generates a highly dynamic, biologically active milieu of plasma-derived molecules that may pass to the airway lumen in vivo. New data on the mechanisms of airway mucosal exudation indicate that the protein systems of circulating plasma may contribute significantly to the biology and immunology of the lamina propria, its surface epithelium and the luminal surface, not only in injured airways, but also in airways that are activated but display no sign of oedema, epithelial disruption, or increased absorption capacity. We suggest that present knowledge of the mechanisms of plasma exudation, together with rapidly emerging information (not detailed herein) on receptors, target cells and cellular responses to the plasma-derived molecules, must be considered in any realistic model that investigates "immuno-inflammatory" mechanisms of the airway mucosa.     

Involvement of hydroxyl radicals in neurogenic airway plasma exudation and bronchoconstriction in guinea-pigs in vivo

1. Cigarette smoke induces plasma exudation in the airways of rodents by activation of capsaicin-sensitive 'sensory-efferent' nerves. The response is mediated predominantly by substance P (SP) and the magnitude of exudation is regulated by neutral endopeptidase (NEP). The component(s) of the smoke responsible for the activation of the nerves may be reactive oxygen radicals. We investigated the effect of the hydroxyl radical scavenger dimethylthiourea (DMTU), a regulator of superoxide anion, superoxide dismutase (SOD), and a regulator of hydrogen peroxide, catalase, on plasma exudation (measured using Evans blue dye) induced by cigarette smoke in guinea-pig main bronchi in vivo. The effect of DMTU on plasma exudation and non-cholinergic bronchoconstriction (measured as pulmonary insufflation pressure, PIP) induced by electrical stimulation of the vagus nerves was also assessed. Interaction between hydroxyl radicals and NEP was assessed with the NEP inhibitor phosphoramidon. 2. In each of the experiments, cigarette smoke increased plasma exudation by approximately 200% above air-exposed controls. Acute administration of DMTU (1.5 g kg-1, i.v. for 20 min) significantly reduced cigarette smoke-induced plasma exudation by 69%. In contrast, neither SOD (240,000 u kg-1, i.v.) nor catalase (400,000 u kg-1, i.v.) significantly affected the exudative response. 3. Chronic pretreatment with DMTU (1.25 g kg-1 over 4 days) significantly reduced bronchial plasma exudation induced by cigarette smoke by 72%. Phosphoramidon (1.5 mg kg-1, i.v.) completely reversed the inhibition by DMTU of cigarette smoke-induced plasma exudation. 4. Vagal stimulation increased plasma exudation by approximately 200% and PIP by approximately 250%. Acute treatment with DMTU had no significant inhibitory effect on these responses, whereas chronic pretreatment inhibited them by approximately 80%. Phosphoramidon reversed the inhibition by chronic DMTU. 5. SP (1 nmol kg-1) increased plasma exudation by approximately 250%, a response which was not inhibited by either acute or chronic DMTU. 6. We conclude that hydroxyl radicals, rather than superoxide anion or hydrogen peroxide, are involved in the induction of neurogenic plasma exudation and bronchoconstriction induced by cigarette smoke or by electrical stimulation of the vagus nerves. These radicals also affect the activity of NEP. Acute DMTU may affect directly the neural actions of hydroxyl radicals contained in the cigarette smoke. Chronic pretreatment with DMTU may inhibit the neurogenic airway responses by effects on tachykinin biosynthesis and/or axonal transport.     

Contribution of plasma-derived molecules to mucosal immune defence, disease and repair in the airways

This review discusses recent observations, in health and disease, on the release and distribution of plasma-derived molecules in the airway mucosa. Briefly, the new data on airway mucosal exudation mechanisms suggest that the protein systems of plasma contribute significantly to the mucosal biology, not only in injured airways but also in such mildly inflamed airways that lack oedema and exhibit no sign of epithelial derangement. Plasma as a source of pluripotent growth factor, adhesive, leucocyte-activating, etc., molecules may deserve a prominent position in schemes that claim to illustrate immunological and inflammatory mechanisms of the airway mucosa in vivo.     

Appearance of airway absorption and exudation tracers in guinea pig tracheobronchial lymph nodes

This study examines the fate of extravasated plasma in inflammatory stimulus-challenged large tracheobronchial airways of ketamine-xylazine-anesthetized guinea pigs. Entry of plasma tracers into the airway lumen was determined by a validated noninjurious airway lavage technique. Removal by airway lymphatics was assessed by tracheobronchial lymph node levels of plasma tracers. Mucosal challenges with histamine (5 nmol), bradykinin (5 nmol), capsaicin (0.4 nmol), or allergen (ovalbumin, 3 pmol) increased the appearance of a plasma tracer (131I-labeled albumin previously injected intravenously) in the airway lumen within 10 min (10-20 times control; P < 0.001), whereas the contractile agent carbachol (8 nmol) was without exudative effect. The mediators were without effect, and capsaicin and allergen only slightly increased the lymph node level of plasma exudation tracer (1.5 times control; P < 0.05). Hence, removal via the lymphatic route of plasma macromolecules may be negligible in the acute and postacute phases of an airway exudation response. Experiments were also carried out with luminally applied macromolecular tracers. These were absorbed from the mucosal surface into the circulation, but a small portion was also transported to the lymph nodes, demonstrating the interconnections between the mucosa and the sampled nodes. Only capsaicin produced an increased node level of absorption tracer. Immunohistochemistry showed that the tracheobronchial tissue and lymph nodes are endowed with nerve fibers containing substance P, the release of which may have mediated lymph transport, vascular, and exudative effects of capsaicin in the present studies.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of putative phospholipase A2 inhibitors on acetic acid-induced acute colitis in the rat

Phospholipase activation may play an important role in ulcerative colitis. This hypothesis was tested by evaluating the effect of two non-selective phospholipase (PL) A2 inhibitors, quinacrine and p-bromophenacyl-bromide (pBPB), on acetic acid-induced colitis in the rat. The calcium antagonist verapamil, which may also act as a PLA2 inhibitor, was also tested. Acute colitis was induced in an isolated colonic segment by instillation of 4 per cent acetic acid for 15 s; this induces a uniform colitis after 4 days. The severity of colitis was evaluated histologically, by measuring myeloperoxidase (MPO) activity and by determining plasma exudation into the lumen of the colon (permeability) with 125I-labelled albumin given intravenously. All three putative PLA2 inhibitors tested were found to prevent the development of colitis. Intravenous administration of quinacrine 10 mg kg-1 at 30 min before instillation of acetic acid resulted in a normal mucosal appearance, normal MPO activity and a significantly reduced increase in plasma exudation into the colon. A similar effect was achieved using verapamil. Intracolonic administration of either quinacrine or pBPB also prevented acetic acid-induced colitis. However, three doses, starting immediately after acetic acid administration and repeated on the first and second days, were needed to achieve this, whereas one dose produced only a partial effect. PLA2 may play an important role in acetic acid-induced colitis and inhibition of its activity may offer an alternative mode of treatment in ulcerative colitis.     

Involvement of leukotrienes in allergic pleurisy in actively sensitized rats: inhibition by the lipoxygenase inhibitor T-0757 of the increase in vascular permeability and leukotriene E4 production

The relative contributions of inflammatory mediators to the increase in vascular permeability in antigen-induced pleurisy were examined in rats actively sensitized with ovalbumin. The effects of various inhibitors were assessed on the exudate volume and plasma exudation rate in the pleural cavity. Two peaks were observed in plasma exudation rate at 0.5 and 3 h after antigen challenge. At 0.5 h, there was a marked decrease in the histamine content of the pleural cells and also a sharp increase in the LTE4 level in the exudate, which was inhibited dose-dependently by the lipoxygenase inhibitor T-0757. Indomethacin and cyproheptadine both depressed exudate volume and exudation rate, whereas T-0757 only reduced the exudation rate. At 3 h, a substantial LTE4 concentration was still detected in the exudate, and the exudation rate was depressed by T-0757 and indomethacin, but not by cyproheptadine. These results suggest that histamine is involved mainly in the early phase, and leukotrienes predominantly contribute to the later phase of exudation. Prostaglandins appear to be involved in both phases. Allergic pleurisy of rats, therefore, may be a suitable model to examine the roles of these inflammatory mediators.     

Cigarette smoke-inhibition of neurogenic bronchoconstriction in guinea-pigs in vivo: involvement of exogenous and endogenous nitric oxide

1. We investigated the effect of acute inhalation of cigarette smoke on subsequent non-adrenergic, non-cholinergic (NANC) neural bronchoconstriction in anaesthetized guinea-pigs in vivo by use of pulmonary insufflation pressure (PIP) as an index of airway tone. The contribution of endogenous nitric oxide (NO) was investigated with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). The contribution of plasma exudation to the response was investigated with Evans blue dye as a plasma marker. 2. Inhalation of 50 tidal volumes of cigarette smoke or air had no significant effect on baseline PIP. In the presence of propranolol and atropine (1 mg kg(-1) each), electrical stimulation of the vagus nerves in animals given air 30 min previously induced a frequency-dependent increase in PIP above sham stimulated controls (16 fold increase at 2.5 Hz, 24 fold increase at 10 Hz). In contrast, in smoke-exposed animals, the increase in subsequent vagally-induced PIP was markedly less than in the air controls (90% less at 2.5 Hz, 76% less at 10 Hz). 3. L-NAME (10 mg kg[-1]), given 10 min before air or smoke, potentiated subsequent vagally-induced (2.5 Hz) NANC bronchoconstriction by 338% in smoke-exposed animals, but had no significant effect in air-exposed animals. The inactive enantiomer D-NAME (10 mg kg[-1]) had no effect, and the potentiation by L-NAME was partially reversed by the NO-precursor L-arginine (100 mg kg[-1]). Vagal stimulation did not affect the magnitude of vagally-induced bronchoconstriction 30 min later. 4. Cigarette smoke exposure reduced the magnitude of subsequent bronchoconstriction induced by neurokinin A (NKA) by 37% compared with the effect of NKA in air-exposed animals. L-NAME had no significant effect on the smoke-induced inhibition of NKA-induced bronchoconstriction. 5. Vagally-induced plasma exudation in the main bronchi was greater in smoke-exposed animals compared with air-exposed animals (120% greater at 2.5 Hz, 82% greater at 10 Hz). 6. We conclude that cigarette smoke-induced inhibition of subsequent NANC neurogenic bronchoconstriction is not associated with inhibition of airway plasma exudation and is mediated in part via exogenous smoke-derived NO, or another bronchoprotective molecule, and by endogenous NO.     

Differing profiles of prostaglandin formation inhibition between selective prostaglandin H synthase-2 inhibitors and conventional NSAIDs in inflammatory and non-inflammatory sites of the rat

The present study examined the inhibitory profiles of NS-398 and nimesulide against prostaglandin (PG) formation in inflammatory and non-inflammatory sites, and compared them with those of aspirin and indomethacin. In vitro, indomethacin inhibited PGH synthase (PGHS)-1 and PGHS-2 almost equally, while NS-398 and nimesulide inhibited only PGHS-2. NS-398 (1, 10 mg/kg) and nimesulide (3 mg/kg) slowed the rate of plasma exudation and thus the exudate accumulation in rat carrageenin-induced pleurisy. Aspirin (30, 100 mg/kg) and indomethacin (10 mg/kg) also reduced this rate. NS-398 and nimesulide reduced the PGE2 more potently than TXB2 and 6-keto-PGF1 alpha in the exudate. However, aspirin and indomethacin did not exhibit this selectivity. The levels of PGE2 correlated significantly with the plasma exudation rate. Moreover, nimesulide (3 mg/kg) did not affect PGE2 formation in rat stomachs injected with 1 M NaCl solution, while indomethacin (10 mg/kg) reduced it. Thus, NS-398 and nimesulide exhibit different inhibitory profiles from aspirin and indomethacin against PG formation. These results suggest that PGE2 may be produced by PGHS-2 in the inflammatory site, and may play a more prominent role than PGI2 in plasma exudation.     

Pharmacological characterization of novel tissue kallikrein inhibitors in vivo

In this study we have investigated the effect of novel tissue kallikreins on the plasma protein exudation induced by porcine pancreatic kallikrein (PPK) in the rabbit skin in vivo. The tissue kallikrein inhibitors here described were synthesized based on analogues of peptide substrates for tissue kallikreins. The intradermal injection of PPK and rabbit urinary kallikrein, but not of rabbit plasma kallikrein, significantly increased the microvascular permeability leading to local oedema formation in the rabbit skin. At the dose of 3-200 nmol/site, the intradermal co-administration of the tissue kallikrein inhibitors Bz-F-F-S-R-EDDnp (Ki = 0.1 microM; ESP5), PAC-F-S-R-EDDnp (Ki = 0.7 microM; ESP6), Bz-F-F-A-P-R-NH2 (Ki = 7.8 microM; ESP8), PAC-F-F-R-P-R-NH2 (Ki = 0.3 microM; ESP9) and Bz-F-F-S-R-NH2 (Ki = 0.3 microM; ESP11) dose-dependently inhibited the plasma protein exudation induced by PPK. The most potent compound was ESP6 (IC25 = 7.8 nmol/site) followed by ESP5 (IC25 = 14.2 nmol/site), ESP8 (IC25 = 25 nmol/site), ESP9 (IC25 = 30 nmol/site) and ESP11 (IC25 = 50.4 nmol/site). The compounds Bz-F-F-R-P-R-NH2 (Ki = 0.5 microM; ESP1), Bz-F-F-pNa (Ki = 0.4 microM; ESP3), Bz-F(NH2)-F-R-P-R-NH2 (Ki = 1.1 microM; ESP7) and Bz-F-F-S-P-R-NH2 (Ki = 4.6 microM; ESP10) had no significant effect on the PPK-induced plasma protein exudation in doses up to 200 nmol/site. ESP6 also inhibited the PPK-induced plasma protein exudation when administered systemically. This compound may constitute a useful tool to further investigate both the physiological and pathological role of tissue kallikreins.     

Vascular changes in rabbit skin induced by proinflammatory phorbol and 12-deoxyphorbol esters

The effects of proinflammatory phorbol and 12-deoxyphorbol esters were determined on blood flow changes and plasma exudation in rabbit skin. Blood flow changes were measured by means of 133Xe washout over that in control-treated sites, while plasma exudation was measured by 131I-labeled human serum albumin leakage from skin blood vessels. 12-Deoxyphorbol-13-phenylacetate, 12-deoxyphorbol-13-angelate, and their C-20 acetates induced vasoconstriction in rabbit skin in doses of 100 ng/site. Tetradecanoyl phorbol acetate indiced vasoconstriction to a far lower degree, while the parent alcohol phorbol and 9,13,14-orthophenylacetyl-resiniferonol had no significant effects on rabbit microvasculature. The ability of tigliane esters to contract rabbit blood vessels was confirmed in vitro in that each of these esters induced a prolonged contraction of superfused rabbit aorta in doses of 1-5 microgram. Plasma exudation in rabbit skin was not significantly increased by the phorbol and 12-deoxyphorbol esters, but in a second determination using 100 ng of PGE1 together with 100 ng of ester, plasma exudations of up to 40 microliter per site were recorded.     

Alterations in hepatic 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase and glucose-6-phosphatase gene expression after hemorrhagic hypotension and resuscitation

Ruscus aculeatus extract (the active principle of Cyclo 3 Fort) is used to increase venous tone in patients with venous disease. In these experiments, the effects of oral Cyclo 3 Fort on capillary permeability were studied in hamsters with moderate diabetes induced by two intraperitoneal injections of streptozotocin (40 mg/kg). Hamsters were treated with a placebo or Cyclo 3 Fort, 2, 10 or 50 mg/kg/day, for 4 weeks starting 3 days after induction of diabetes. Intravital microscopy of cheek pouch preparations was performed using fluorescein-labelled dextran (FITC-dextran) as a marker for plasma exudation (leak formation). Plasma levels of glucose were measured prior to experiments. Following preparation for intravital microscopy, each cheek pouch was subjected to two applications of histamine, 5 x 10(-6) M for 5 min at 30-minute intervals. Plasma exudation (number of leaks/cm2) was significantly reduced in animals receiving Cyclo 3 Fort at doses of 10 mg/kg or above. The mean number of leaks was 258 +/- 17 in the placebo group, compared with 253 +/- 12, 125 +/- 7 (p < 0.01) and 99 +/- 7 (p < 0.01) in animals receiving Cyclo 3 Fort, 2, 10 or 50 mg/kg, respectively. Blood glucose levels did not differ between groups. Thus, oral Cyclo 3 Fort inhibited histamine-induced plasma exudation in hamsters with mild diabetes without affecting the glycaemia.     

Role of endogenous nitric oxide in allergen-induced airway responses in guinea-pigs

1. Endogenous nitric oxide (NO) can be detected in exhaled air and accumulates in inflamed airways. However its physiological role has not been fully elucidated. In this study, we investigated a role for endogenous NO in allergen-induced airway responses. Sensitised guinea-pigs were treated with NG-nitro-L-arginine methyl ester L-NAME (2.0 mM) or aminoguanidine (AG) (2.0 mM) 30 min before the allergen challenge, and 3 and 4 h after the challenge. Alternatively, L-arginine (2.4 mM) treatment was performed 30 min before, and 2 and 3 h after the challenge. In all groups, ovalbumin (OVA) challenge (2 mg ml(-1) for 2 min) was performed, and airway responses, NO production, infiltration of inflammatory cells, plasma exudation and histological details were examined. 2. Allergen-challenged animals showed an immediate airway response (IAR) and a late airway response (LAR), which synchronised with an increase in exhaled NO. Treatment with L-NAME and AG did not affect IAR while they significantly blocked LAR (72% and 80% inhibition compared to vehicle) and production of NO (35% and 40% inhibition). On the other hand, treatment with L-arginine did not affect IAR but potentiated LAR (74% augmentation). 3. In bronchoalveolar lavage (BAL) fluid, allergen-induced increases in eosinophils were reduced by 48% for L-NAME treatment compared to vehicle, and increased by 56% for L-arginine treatment. 4. Treatment with L-NAME significantly decreased airway microvascular permeability to both Monastral blue (MB) and Evans blue (EB) dye (50.6% and 44% inhibition). 5. We conclude that allergen-induced LAR is closely associated with NO production, and that NO plays a critical role in inflammatory cell infiltration and plasma exudation in the allergic condition.     

An essential role for free radicals and derived species in signal transduction

OBJECTIVE: To examine whether there is generation of oxygen free radicals (OFR) and lipid peroxidation of cell membrane after volume replacement for burn shock, and to study the relationship between OFR injury and enterogenous endotoxemia. METHODS: Forty-seven burn patients were involved in this study. Among them, 18 had delayed fluid resuscitation (DR) and the others had early fluid resuscitation (ER) within 6 hours postburn. Sixty-six gnotobiotic rats were used in a collaborating experiment as burn models. They were divided into 4 groups: sham injury (n = 6), early resuscitation (n = 24), late resuscitation (n = 24) and vitamins E and C treatment group (n = 12). All the rats, except those in the sham injury group, were inflicted with 40% total body surface area (TBSA) third-degree burns. OFR was determined in the blood of patients with electron spin resonance (ESR). S/W ratio and tau c values of patients' erythrocytes were measured with ESR spectrometer. Blood superoxide dismutase (SOD) and glutathione peroxidase (GSHPx) activities, malondialdehyde contents and plasma endotoxin levels were assayed. Rats were sacrificed at the 12th, 24th, 48th and 72nd hour after injury. Plasma endotoxin levels, mucosal SOD, GSHPx and malondialdehyde (MDA), as well as diamine oxidase activity of ileum were determined. Cultures of mesenteric lymph nodes (MLN), liver, spleen, heart, lung, kidney and blood were done. RESULTS: A significant increase in blood OFR contents and plasma MDA, and a significant decline in blood SOD and GSHPx were found after resuscitation in DR group as compared with those in ER group. Both strong to weak spectra component (S/W) ratio and tau c value were higher in DR group in contrast with those in ER group. Higher elevation in plasma endotoxin level in DR group was seen. In DR group, plasma MDA content was correlated with S/W ratio, tau c value and plasma endotoxin level. In rats, the level of mucosal MDA, plasma endotoxin and incidence of bacterial translocation (BT) were significantly higher. Mucosal SOD, GSHPx and diamine oxidase (DAO) activity were significantly lower in DR group as compared with those in ER group. In DR group, mucosal MDA content was negatively correlated with mucosal DAO activity, while the latter was negatively correlated with BT. After treatment with vitamins E and C, mucosal MDA content decreased, plasma endotoxin and BT significantly declined and mucosal DAO heightened. CONCLUSIONS: Tissue reperfusion might induce the production of OFR, resulting in lipid peroxidation injury, especially to intestinal mucosa, and resulting in disruption of mucosal barrier function followed by endotoxemia and BT.     

Plasma and mucosal fatty acid pattern in colectomized ulcerative colitis patients

Patients with inflammatory bowel disease (IBD) have increased plasma n3 polyunsaturated fatty acids (PUFAs), which in ulcerative colitis (UC) patients persists six months after colectomy, suggesting a primary abnormality in fatty acid (FA) metabolism in IBD. This finding needed to be confirmed in a larger series of UC long-term colectomized patients. We aimed to assess the plasma FA pattern in UC colectomized patients with either Brooke's ileostomy (UC-BI) or ileal pouch anal anastomosis (UC-IPAA) and the mucosal FA pattern in the ileal reservoir of the UC-IPAA patients. Plasma FAs were assessed in 63 UC colectomized patients (31 with BI and 32 with IPAA) and 30 controls. In 26 UC-IPAA (8 with pouchitis and 18 without pouchitis) and in 13 healthy controls gut mucosal FAs were also investigated. FAs were detected by capillary column gas-liquid chromatography. Increased levels of saturated fatty acids (SFAs) and decreased percentages of monounsaturated fatty acids (MUFAs) were observed in both groups of patients. There were no changes in plasma n3 and n6 PUFAs. The mucosal FA pattern of the ileal reservoir consisted of increased long-chain PUFAs, specially n6 PUFA, and a decrease of their essential precursors. High percentages of SFAs and low percentages of MUFAs were also seen. The plasma FA profile previously described in IBD is not observed long-term after colectomy in UC, suggesting that it is related with the presence of inflamed intestine. High concentrations of SFAs and decreased percentages of MUFAs might represent early events in disturbed FA metabolism in IBD. The changes in FAs of the ileal reservoir, which closely resemble those found in human and experimental IBD, probably represent a common pattern of intestinal inflammation.     

Nasal symptoms and indices of nasal inflammation in flour-dust-exposed bakers

OBJECTIVE: To analyze whether indices of nasal airway inflammation in bakers were related to nasal symptoms and exposure to airborne flour dust. METHODS: A cross-sectional study was performed in 12 currently flour-exposed bakers. They were examined by nasal lavage (NAL), visual inspection, a test of mucociliary clearance, and nasal peak expiratory flow (nasal PEF). NAL fluid was analyzed according to the inflammatory markers eosinophil cationic protein (ECP), indicating eosinophilic activity; myeloperoxidase (MPO), indicating active neutrophils; hyaluronic acid (HA) from active fibroblasts; tryptase, indicating activation of mast cells; and albumin, indicating plasma exudation. The bakers were also questioned about respiratory symptoms and working history. Their current and cumulative exposure to inhalable flour dust was estimated after exposure measurements and information about earlier work tasks. Office workers (n=16) without occupational exposure to dust or any other known nasal irritant or sensitizer served as controls. RESULTS: Personal inhalable dust measurements among the bakers working as dough makers or bread formers ranged from 1.0 to 3.8 mg/m3. Of the 12 bakers, 10 reported at least 1 nasal symptom (crusts, blockage, or a runny nose), a proportion significantly greater than that of the controls (P=0.009). Bakers with nasal symptoms had higher concentrations of markers of inflammation in their NALs as compared with nonsymptomatic bakers. The difference was significant for MPO (P=0.02) and HA (P=0.04) in relation to a runny nose. Tryptase was detected in only one NAL of the bakers. There was a positive correlation between the cumulative dose of inhalable flour dust and concentrations of MPO and HA in NAL. Two bakers were sensitized to wheat; they had the highest NAL concentrations of inflammatory markers. CONCLUSIONS: Our results indicate that flour dust exposure in bakers at levels below the current occupational exposure limit causes nasal mucosal inflammation, which, in turn, is related to nasal symptoms. We propose that the inflammation may be nonallergic, characterized by activation of neutrophils and fibroblasts.     

Results of initial surgery and adjuvant chemotherapy in treating small-cell lung cancer

The changes in the intestinal mucosal permeability were observed by quantitatively assessing plasma to luminal clearance of 99mTc-labeled DTPA, and the influence of platelet activating factor (PAF) on it was investigated. The results showed that intestinal permeability was significantly elevated after severe burn and was positively correlated with increase in PAF in the intestinal tissue (r = 0.94, P < 0.01). PAF antagonist therapy could significantly attenuate postburn intestinal mucosal permeability. It is concluded that PAF is one of the important factors causing increased intestinal permeability after severe burn.     

Immune parameters in athletes before and after strenuous exercise

Secretory IgA levels were studied in nationally ranked Nordic skiers before and after the national cross-country races held in February 1981. Comparing the skiers with age-matched controls, there was significantly lower level of salivary IgA before the race. Concentrations of IgA decreased further following the competition (50 kn for males; 20 km for females) to very low levels. There also were a significant increase in the percentage of B lymphocytes and a decrease in the null population (non-T, non-B) in the athletes after the race compared with the controls. The mechanism responsible for these changes is unknown, but the low salivary IgA levels may result from depletion of nasal fluid and/or malfunction of the mucosal plasma cells due to a decrease temperature in the mucous membranes. We speculated that a temporary antibody deficiency on the mucosal surface might lead to a susceptibility to acquiring viral and bacterial infections, especially during the interval immediately following strenuous exercise.     

Effect of ileo-jejunal transposition on the growth of the GI tract and pancreas in young and aged rats

BACKGROUND: Ileo-jejunal transposition (IJT; transposition of the distal quarter of the small intestine into the proximal jejunum) is known to stimulate mucosal growth of the transposed ileum, but the effects on other parts of the small intestine are controversial. The effect of aging on the trophic action of IJT is not known. METHODS: We examined the trophic effect of IJT (3 weeks post-operation) on the gastrointestinal tract and pancreas, and on plasma levels of neurotensin and gastrin in three different aged groups of Fischer 344 rats (4, 12, and 24 months old). RESULTS: Three weeks after IJT, the mucosal mass, villus height, and crypt depth increased significantly in the transposed ileum as well as in the remainder of the small intestine. The weights of the colon and pancreas increased significantly after IJT. These responses were not affected by aging. In each of the three age groups, IJT did not affect plasma gastrin level, but significantly increased plasma level of neurotensin. CONCLUSIONS: The distal ileum appears to play an important role in the regulation of growth in the intestine and pancreas; this role is preserved in aged rats. Neurotensin may play an important role in this mechanism.     

Mucosal mast cells and the allergic response against nematode parasites

IgE-mediated Type-I allergic reactions at nematode-infected mucosal surfaces are considered to have a direct protective function. The contribution of mucosal mast cells (MMC) to these mucosal allergic responses is reviewed. In addition to the T helper 2 cell-mediated regulation of MMC hyperplasia during nematode infection the kit ligand, stem cell factor (SCF), plays a key role in the early development of the MMC response. Studies in the mouse suggest that MMC protect against certain nematodes which enter the mucosa but not against lumen dwelling nematodes. The protective roles of MMC in other species, including sheep, are less certain and there is some evidence that MMC might enhance parasite fecundity. The measurement of MMC-specific granule chymases released systemically, and into the gut lumen, permits precise monitoring of mast cell activation and suggests that the secreted chymases may target epithelial junctional complex proteins, thereby causing increased mucosal permeability. The abundant intraepithelial MMC found in parasitised mucosa may, therefore, serve as epithelial gatekeepers permitting the translocation of plasma proteins onto the mucosal surface.     

Gamma knife radiosurgery and albendazole for cerebral alveolar hydatid disease

We measured pharyngeal mucosal pressures at six different locations on the laryngeal mask airway (LMA) and tested the hypothesis that the efficacy of the seal is not related to pharyngeal mucosal pressure. Twenty anesthetized, paralyzed adult patients were studied. Microchip sensors were attached to the size 5 LMA at locations corresponding to the lateral and posterior pharynx, the hypopharynx, the pyriform fossa, the base of tongue, and the oropharynx. Mucosal pressures and airway sealing pressures were recorded during inflation of the cuff from 0 to 40 mL in 10-mL increments. The highest mean mucosal pressure was in the oropharynx (26 cm H2O), and the lowest was in the posterior pharynx (2 cm H2O). Mucosal pressures increased with increasing intracuff pressure and cuff volume, but the rate of increase varied among locations. Airway sealing pressure increased with increasing intracuff volume from 0 to 10 mL (P < 0.0001) and 10 to 20 mL (P = 0.0001), was unchanged from 20 to 30 mL, and decreased from 30 to 40 mL (P = 0.005). The airway sealing pressure was higher than pharyngeal mucosal pressure until the intracuff volume was > or =30 mL. There was no correlation between mucosal pressures and airway sealing pressure at any location. We conclude that the efficacy of the seal is not related to pharyngeal mucosal pressure. Pharyngeal mucosal pressures are generally lower than those considered safe for the tracheal mucosa during prolonged intubation. IMPLICATIONS: We measured pharyngeal mucosal pressures at six different locations on the laryngeal mask airway and showed that the efficacy of the seal is not related to pharyngeal mucosal pressure. Pharyngeal mucosal pressures are generally lower than those considered safe for the tracheal mucosa during prolonged intubation.