Biomedical subjects

C M Lilly

Publications and source records attributed to C M Lilly.

At least 37 records · Page 2Linked to original sources

PubMed1997

Expression of eotaxin by human lung epithelial cells: induction by cytokines and inhibition by glucocorticoids.

Eotaxin is a potent and specific eosinophil chemoattractant that is mobilized in the respiratory epithelium after allergic stimulation. Pulmonary levels of eotaxin mRNA are known to increase after allergen exposure in sensitized animals. In this study we demonstrate that TNF alpha and IL-1beta induce the accumulation of eotaxin mRNA in the pulmonary epithelial cell lines A549 and BEAS 2B in a dose-dependent manner. Cytokine-induced A549 cell mRNA accumulation was maximal at 4 h and was significantly enhanced when the cells were costimulated with IFNgamma. TNFalpha- and IL-1beta-induced increases in eotaxin mRNA were diminished in a dose-dependent manner by the glucocorticoid dexamethasone and were augmented by the protein synthesis inhibitor cycloheximide. Cytokine-induced increases in eotaxin mRNA expression correlated with increased eotaxin protein production and secretion, and dexamethasone inhibition of cytokine-induced eotaxin mRNA augmentation was associated with diminished eotaxin protein secretion. These findings, together with the known kinetics of TNF alpha and IL-1beta mobilization in asthmatic airways and the potent eosinophil chemotactic effects of eotaxin, define a mechanism linking inflammatory cytokine mobilization to eosinophil recruitment that may be relevant to the pathogenesis of asthma.

Animals↗

PubMed1997

Interferon gamma induces prostaglandin G/H synthase-2 through an autocrine loop via the epidermal growth factor receptor in human bronchial epithelial cells.

The induction of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) by proinflammatory cytokines accounts, at least in part, for the altered eicosanoid biosynthesis in inflammatory diseases. In secondary cultures of normal human bronchial epithelial cells (NHBECs), interferon-gamma (IFN-gamma, 10 ng/ml for 24 h) increased the amount of prostaglandin E2 (PGE2) released in response to stimulation with exogenous arachidonic acid (5 microM). The enhanced production of PGE2 reflected the upregulation of PGHS-2 as indicated by enhanced expression of PGHS-2 RNA and increased recovery of PGHS-2 protein in NHBECs. IFN-gamma did not alter the production of PGE2 in A549 cells (a human lung adenocarcinoma cell line) or 6-keto-PGF1alpha in human umbilical vein endothelial cells (HUVECs), although prostaglandin release and/or the expression of PGHS-2 RNA in these cell lines was upregulated by other proinflammatory cytokines. Induction of PGHS-2 RNA in IFN-gamma-treated NHBECs, which peaked at 24 h, suggested the presence of an intermediary substance regulating the expression of PGHS-2. When the binding between the epidermal growth factor (EGF) receptor and its ligands was disrupted by a neutralizing antibody (LA-1), IFN-gamma failed to upregulate the release of PGE2 and the expression of PGHS-2 RNA in NHBECs. Furthermore, IFN-gamma induced the expression of RNAs for a number of ligands at the EGF receptor TGF-alpha; heparin-binding EGF-like growth factor (HB-EGF); and amphiregulin in NHBECs, and when administered exogenously, these ligands increased PGE2 release from NHBECs. Heparin at the concentration that neutralized the function of amphiregulin, or antibodies against TGFalpha or HB-EGF also reduced the release of PGE2 from IFN-gamma-stimulated NHBECs. These data are consistent with the presence of an autocrine growth factor/EGF receptor loop regulating PGHS-2 expression and PGE2 synthesis in bronchial epithelial cells.

6-Ketoprostaglandin F1 alpha↗

PubMed1997

Acute and chronic effects of allergic airway inflammation on pulmonary nitric oxide production.

Nitric oxide (NO) is thought to be an important modulator of airway function in normal and inflamed airways. We investigated the acute and chronic effects of induced allergic airway inflammation on NO levels in mixed expired gas and NO synthase (NOS) expression in guinea pigs and the relationship between airway responses and NO production. Airway inflammation was induced by repeated aerosolized antigen exposure, and its presence was confirmed by bronchoalveolar lavage. Acute antigen exposure in sensitized animals produced a fivefold increase in respiratory resistance over baseline that was associated with a cotemporal increase in expired NO (17 +/- 1 to 56 +/- 8 parts per billion, P < 0.01). A continuous subcutaneous infusion of nitro-L-arginine methyl ester (L-NAME), a competitive inhibitor of NOS, markedly decreased expired NO (P < 0.01) and resulted in a significantly greater rise in resistance following antigen challenge (660 +/- 60 vs. 497 +/- 42% of baseline in non-L-NAME-treated animals, P < 0.05). These data support the hypothesis that endogenous pulmonary NO production, as reflected by expired NO, has an important homeostatic role in acute allergic bronchoconstriction.

Acute Disease↗

PubMed1997

Endogenous nitric oxide and allergic bronchial hyperresponsiveness in guinea pigs.

To address the role of endogenous pulmonary nitric oxide (NO) in the modulation of airway tone, we investigated changes in expired NO levels, measured by chemiluminescence, and the effect of inhibition of NO synthase on inflammation-associated bronchial hyperresponsiveness in guinea pigs. Mixed expired gas NO levels were similar at baseline in antigen-exposed and unexposed animals and increased transiently to a similar degree during histamine-induced bronchoconstriction in both groups of animals [155 +/- 12% (15 +/- 1 to 23 +/- 4 ppb, P < 0.01) and 162 +/- 19% (16 +/- 2 to 25 +/- 3 ppb, P < 0.01) of baseline, respectively, after administration of 30 nmol/kg histamine]. Although inhibition of NO synthase with intravenous NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg) enhanced bronchial responsiveness to histamine by 30 +/- 8% in unexposed animals (P < 0.05), L-NAME did not enhance histamine responsiveness in antigen-exposed animals exhibiting bronchial hyperresponsiveness 24 h after antigen exposure. Thus bronchial hyperresponsiveness induced by repeated pulmonary antigen exposure may be associated with a transient defect in NO-related homeostatic bronchodilator activity.

Animals↗

PubMed1997

Respiratory transfer impedance between 8 and 384 Hz in guinea pigs before and after bronchial challenge.

We report a forced oscillatory technique for noninvasively measuring respiratory transfer impedance (Ztr) between 8 and 384 Hz in guinea pigs. This technique uses a device consisting of two chambers: one surrounding the animal's head that is used as a plethysmograph to measured flow through the airway opening and the other that surrounds the animal's body and is used to apply pressure oscillations to the body surface. Ztr was measured in spontaneously breathing awake guinea pigs and while the animals were anesthetized in normal and methacholine-challenged conditions. An eight-element model consisting of an airway compartment separated from a tissue compartment by a shunt gas compression compartment was fit to the data. Anesthesia increased central and peripheral airway resistance and bronchial airway wall compliance by 13, 31, and 44%, respectively, whereas it decreased tissue compliance by 37%. Compared with the unanesthetized condition, the methacholine challenge (20 micrograms/kg) resulted in an increase in central and peripheral airway resistance (69 and 319%, respectively) and a decrease in bronchial airway wall and tissue compliance (37 and 79%, respectively). This technique is capable of measuring Ztr in anesthetized and awake guinea pigs. Analysis of these data with this eight-element model provides reasonable estimates of airway and tissue parameters.

Airway Resistance↗

PubMed1996

Effects of interleukin 5-induced pulmonary eosinophilia on airway reactivity in the guinea pig.

Administration of interleukin 5 (IL-5) to guinea pigs by tracheal injection was associated with increased recovery of eosinophils and neutrophils from bronchoalveolar lavage (BAL) fluid. The number of eosinophils recovered from BAL fluid increased in a dose-dependent manner from 9 +/- 2 X 10(3)/ml to a plateau of 143 +/- 29 X 10(3)/ml after the administration of recombinant human IL-5 (rhIL-5). Tracheal administration of recombinant guinea pig IL-5 (gpIL-5) also increased eosinophil recovery but was less potent than rhIL-5. Histological analysis confirmed the presence of inflammatory cells in the lung; there were higher grades of inflammation in airway than in parenchymal tissue after gpIL-5 administration. In addition, the histological grade of airway inflammation was greater 24 and 72 h after gpIL-5 administration than it was 6 days after administration. Airway hyperresponsiveness is reported to occur in guinea pigs exposed to rhIL-5 by intraperitoneal cellular production. It is surprising that airway infiltration with eosinophils induced by the topical application of IL-5 was not associated with hyperresponsiveness to substance P, histamine, or platelet-activating factor in intact animals or to methacholine in tracheally perfused lungs. Furthermore, the microvascular leakage induced by substance P was not altered by rhIL-5 administration. These findings indicate that the presence of eosinophils alone is not sufficient for the expression of airway hyperresponsiveness. Our ability to separate eosinophil recruitment and retention in the tissues from airway hyperresponsiveness indicates that these two processes are distinct and that the presence of eosinophils in lung tissue, by itself, is not sufficient to alter airway contractile responses.

Animals↗

PubMed1996

Production and characterization of guinea pig IL-5 in baculovirus-infected insect cells.

To study the role interleukin (IL)-5 may play in altering airway function in asthma, we have produced recombinant protein for exogenous administration to guinea pigs. The guinea pig IL-5 (gpIL-5) cDNA was cloned by polymerase chain reaction (PCR) amplification of guinea pig spleen RNA and expressed as a secretion product from recombinant baculovirus-infected Sf9 insect cell cultures. The protein was purified to homogeneity by a four-step procedure that included immunoaffinity chromatography using polyclonal antipeptide antibodies against a region of the mature secreted cytokine. The cytokine was properly processed after the signal sequence by the Sf9 cells, was glycosylated with terminal mannose-containing oligosaccharide, and had proper disulfide-linked dimer structure as determined by sodium dodecyl sulfate-polyacrylamide gel electrophoresis. The purified preparation was active in vitro and in vivo as determined by its ability to prime human basophils to release leukotriene C4 in the presence of C5a and to induce airway eosinophilia in naive guinea pigs.

Animals↗

PubMed1996

Prostaglandin G/H synthase-2 is the constitutive and dominant isoform in cultured human lung epithelial cells.

Two isoforms of prostaglandin G/H synthase (PGHS; prostaglandin endoperoxide synthase, cyclooxygenase) have been identified; PGHS-1 is expressed constitutively in most tissues, whereas PGHS-2 is thought to be induced by various proinflammatory cytokines and growth factors. In this study, we determined which isoform of PGHS mRNA, protein, and activity was present constitutively in A549 (a human lung adenocarcinoma cell line) and in untransformed (normal human bronchial epithelial or NHBE) and transformed (16HBE4o-) human bronchial epithelial cells. Two PGHS-2-specific inhibitors, NS-398 and L-745, 337, blocked the release of prostaglandin E2 from A549 cells with mean inhibitory concentrations of 5 and 18 nM, respectively, but did not inhibit its release from human bronchial smooth muscle cells (BSMC) at a concentration of 10 microM. Northern and immunoblot analysis demonstrated that BSMC expressed PGHS-1 mRNA and protein constitutively, whereas epithelial cells expressed PGHS-2 mRNA and protein constitutively with either undetectable (A549, 16HBE4o-) or very low levels (NHBE) of PGHS-1. We conclude that PGHS-2 is the dominant PGHS isoform in unstimulated and stimulated lung epithelial cells in culture.

Base Sequence↗

PubMed1996

Elevated nitric oxide concentrations in isolated lower airway gas of asthmatic subjects.

Previous studies have raised the possibility that the measurement of nitric oxide (NO.) concentrations in expired air may represent a noninvasive measure of lower airway inflammation. To address the question of whether the elevated NO. recovered in mixed expired air from asthmatic subjects is a reflection of the pulmonary airway microenvironment or merely nasopharyngeal contamination, mixed expired NO. determinations were performed in five normal and five asthmatic subjects before and after orotracheal intubation (thereby isolating the lower airway gas from ambient air contamination or gas conditioned in the nasopharynx). The mixed expired NO. concentrations determined in patients with asthma were significantly elevated (p < 0.05 or less) above those of normal subjects in both the pre- and postintubation samples. After intubation, mixed expired NO. levels were 4.7 +/- 1.3 ppb and 13.2 +/- 2.0 ppb in normal and asthmatic individuals, respectively; the difference in these values was statistically significant (p < 0.01). Lower airway gas, sampled through the bronchoscope during a breathhold, was found to contain NO. concentrations of 7.0 +/- 1.2 ppb and 40.5 +/- 5.6 ppb at the tracheal carina of normal and asthmatic individuals, respectively. The asthmatic values were significantly (p < 0.01) elevated above those found in normal subjects. These findings indicate that the difference in mixed expired NO. of normal subjects and asthmatics reflects a difference in NO. concentration present in the lower airway.

Adult↗

PubMed1996

Urinary leukotriene E4 levels increase upon exposure to hypobaric hypoxia.

STUDY OBJECTIVE: To determine whether urinary leukotriene E4 (uLTE4) levels increase upon exposure to high altitude, and also to ascertain the relationship between uLTE4 levels and symptoms of acute mountain sickness (AMS). DESIGN: Prospective, unblinded, single-factor (altitude) experimental study. SETTINGS: US Army research laboratory facilities at sea level ([SL] 50 m), 1,830 m, and 4,300 m. PARTICIPANTS: Eight healthy male subjects ranging in age from 19 to 24 years. MEASUREMENTS: uLTE4 levels and symptoms of AMS were measured at just above SL (50 m), 3 1/2 days after being transported from SL to moderate altitude (MA) (1,830 m), and 1 1/2 days after ascent from 1,830 to 4,300 m (high altitude [HA]). Symptoms of AMS were assessed using standard indexes derived from the Environmental Symptoms Questionnaire weighted toward cerebral (AMS-C) and respiratory (AMS-R) manifestations. Oxygen saturation was measured noninvasively by pulse oximetry at SL and HA. RESULTS: The mean (+/-SEM) uLTE4 levels (pg/mg creatinine) were 67.9 (+/-13.2) at SL; 82.3 (+/-5.5) at MA; and 134.8 (+/-19.4) at HA (p < 0.05 comparing HA with SL and MA). CONCLUSIONS: We conclude that uLTE4 levels increase shortly after exposure to HA even after staging for 4 days at MA. Although this study does not clearly demonstrate a relationship between uLTE4 levels and symptoms of AMS, it supports the hypothesis that leukotrienes may be involved in the pathophysiologic state of AMS.

Adult↗

PubMed1995

Constitutive and allergen-induced expression of eotaxin mRNA in the guinea pig lung.

Eotaxin is a member of the C-C family of chemokines and is related during antigen challenge in a guinea pig model of allergic airway inflammation (asthma). Consistent with its putative role in eosinophilic inflammation, eotaxin induces the selective infiltration of eosinophils when injected into the lung and skin. Using a guinea pig lung cDNA library, we have cloned full-length eotaxin cDNA. The cDNA encodes a protein of 96 amino acids, including a putative 23-amino acid hydrophobic leader sequence, followed by 73 amino acids composing the mature active eotaxin protein. The protein-coding region of this cDNA is 73, 71, 50, and 48% identical in nucleic acid sequence to those of human macrophage chemoattractant protein (MCP) 3, MCP-1, macrophage inflammatory protein (MIP) 1 alpha, and RANTES, respectively. Analysis of genomic DNA suggested that there is a single eotaxin gene in guinea pig which is apparently conserved in mice. High constitutive levels of eotaxin mRNA expression were observed in the lung, while the intestines, stomach, spleen, liver, heart, thymus, testes, and kidney expressed lower levels. To determine if eotaxin mRNA levels are elevated during allergen-induced eosinophilic airway inflammation, ovalbumin (OVA)-sensitized guinea pigs were challenged with aerosolized antigen. Compared with the lungs from saline-challenged animals, eotaxin mRNA levels increased sixfold within 3 h and returned to baseline by 6 h. Thus, eotaxin mRNA levels are increased in response to allergen challenge during the late phase response. The identification of constitutive eotaxin mRNA expression in multiple tissues suggests that in addition to regulating airway eosinophilia, eotaxin is likely to be involved in eosinophil recruitment into other tissues as well as in baseline tissue homing.

Allergens↗

PubMed1995

Diurnal variation of urinary leukotriene E4 and histamine excretion rates in normal subjects and patients with mild-to-moderate asthma.

BACKGROUND: Leukotriene E4 (LTE4) and histamine excreted into the urine reflect the in vivo synthesis and release of cysteinyl leukotrienes and histamine, respectively. We examined the diurnal variation of the excretion rate of these mediators over 4 consecutive days in normal subjects (n = 5) and patients with stable mild-to-moderate asthma (n = 8). METHODS: Sixteen consecutive 6-hour urine samples were collected over 4 days. Urinary LTE4 concentrations were determined by reverse-phase high-pressure liquid chromatography, followed by ELISA. Urinary histamine concentrations were measured by ELISA. The excretion rates of these compounds were normalized relative to urinary creatinine content. RESULTS: The mean urinary LTE4 excretion rate was 83.8 +/- 38.2 pg/mg creatinine (mean +/- SD) in normal subjects; in patients with asthma, the urinary LTE4 excretion rate (110.0 +/- 59.2 pg/mg creatinine) was significantly higher than that in normal subjects (p < 0.05). The urinary histamine excretion rate was not different between normal subjects (24.0 +/- 12.5 ng/mg creatinine) and patients with asthma (31.5 +/- 25.8 ng/mg creatinine). A robust and systematic within-day variation (p < 0.01), but no day-to-day variation, was observed in histamine excretion rate. Although the magnitude of variation in LTE4 excretion within a day was significantly greater in patients with asthma than in normal subjects (p < 0.05), we could not identify any specific diurnal variation pattern in either the normal or the asthma group. No significant correlation was observed between urinary LTE4 and histamine excretion rate within any subject. CONCLUSIONS: Patients with asthma excrete LTE4 in the urine at a greater rate than normal subjects. Although no systematic variation in urinary LTE4 excretion rates over the course of a day was observed in either normal subjects or patients with stable asthma, the presence of a systematic diurnal variation of urinary histamine excretion exists in both groups.

Adult↗

PubMed1995

Hospitalizations for respiratory syncytial virus infection in Alaska Native children.

To characterize the epidemiology of Alaska Native children hospitalized for respiratory syncytial virus infections, we reviewed records of hospitalizations during the winter seasons of 1991 to 1992 and 1992 to 1993 at a hospital in Anchorage and a rural hospital in the Yukon Kuskokwim Delta (YKD) region of southwestern Alaska. The median age of hospitalization for respiratory syncytial virus infection was 2 months of age for YKD residents and 4.5 months for Anchorage residents. Sixteen percent of the hospitalized YKD children were less than 1 month of age, whereas the same was true for only 3% of the Anchorage children. Eight percent of the YKD patients required mechanical ventilation, whereas none of the Anchorage patients required ventilation. The median hospital stay was 4.8 days for YKD patients and 3.2 days for Anchorage patients. Hospitalization rates for infants less than 1 year of age were 33/1000 for Alaska Natives in Anchorage and 100/1000 for those in the YKD region. The extremely high hospitalization rate, especially among very young infants in the rural YKD region, points to a need for early preventive efforts.

Age Factors↗

PubMed1995

Substance P-induced histamine release in tracheally perfused guinea pig lungs.

The capacity of substance P (SP) and endogenously released tachykinins to liberate histamine was examined in isolated tracheally perfused guinea pig lungs. Increasing doses of tracheally injected SP were associated with the recovery of increasing amounts of histamine from lung effluent. The mechanism of SP-induced histamine liberation was explored in studies with neurokinin-(NK) receptor agonists and antagonists. Tracheal injection of either the NK1 agonist [Sar9,Met(O2)11]SP or the NK2 agonist [beta-Ala8]-neurokinin A-(4-10) was associated with a significant increase in histamine recovery from lung effluent. In addition, both the NK1 antagonist CP-99994 and the NK2 antagonist SR-48968 significantly inhibited SP-induced histamine release. These findings support the hypothesis that SP can liberate histamine from guinea pigs lungs by a mechanism that depends predominantly on NK1- and NK2-receptor activation. The liberation of endogenous tachykinins by acute tracheal injection of capsaicin was also associated with augmented histamine recovery, which was inhibited by combined NK1- and NK2-receptor blockade. Tracheal injection of SP was associated with an increase in the percentage of airway mast cells exhibiting histological evidence of degranulation. This study demonstrates that exogenous SP, as well as endogenous tachykinins released from capsaicin-sensitive neurons, can liberate histamine, most likely from airway mast cells, by a mechanism that depends predominantly on the activation of NK1 and NK2 receptors.

Animals↗

PubMed1995

Neuropeptide content of lungs from asthmatic and nonasthmatic patients.

Tracheal and lung parenchymal SP-LI (substance P-like immunoreactivity) and VIP-LI (vasoactive intestinal peptide-like immunoreactivity) content was measured in HPLC-purified tissue extracts from patients with and without asthma. We detected significantly less SP-LI in tracheal tissue from asthmatic than from nonasthmatic patients, whereas parenchymal SP-LI content was not significantly different between these groups. This finding does not support the concept that asthmatic lungs contain excessive amounts of SP. Indeed, lower SP-LI content of tracheal tissues from asthmatic patients may reflect augmented SP release followed by degradation. We detected greater quantities of VIP-LI in tracheal than in parenchymal tissue in both groups, but did not detect significant differences in VIP-LI content in tracheal or parenchymal tissues from asthmatic and nonasthmatic patients. These findings indicate that asthmatic and nonasthmatic lungs contain similar levels of VIP.

Adolescent↗

PubMed1994

Constitutive and inducible nitric oxide synthase gene expression, regulation, and activity in human lung epithelial cells.

Histochemical activity and immunoreactivity of nitric oxide synthase (NOS, EC 1.14.13.39) have been recently demonstrated in human lung epithelium. However, the molecular nature of NOS and the regulation and function of the enzyme(s) in the airway is not known. A549 cells (human alveolar type II epithelium-like), BEAS 2B cells (transformed human bronchial epithelial cells), and primary cultures of human bronchial epithelial cells all exhibited constitutive NOS activity that was calcium dependent and inhibitable by the NOS inhibitor NG-monomethyl-L-arginine. Nitric oxide production by epithelial cells was enhanced by culture in the presence of interferon gamma, interleukin 1 beta, tumor necrosis factor alpha, and lipopolysaccharide; the NOS activity expressed under these conditions showed less dependence on calcium, reminiscent of other inducible forms of NOS. Two distinct NOS mRNA species, homologous to previously identified constitutive brain (type I) and inducible hepatic (type II) NOS, were demonstrated by reverse transcription-polymerase chain reaction in all cell lines. Northern analysis confirmed the expression of inducible NOS mRNA. Cell culture with epidermal growth factor, a principal regulator of epithelial cell function, decreased inducible NOS activity by posttranscriptional action but did not affect constitutive NOS activity. The coexistence of constitutive and inducible NOS in human alveolar and bronchial epithelial cells is consistent with a complex mechanism evolved by epithelial cells to protect the host from microbial assault at the air/surface interface while shielding the host from the induction of airway hyperreactivity.

Adenocarcinoma↗

PubMed1994

Direct evidence for a role of the mast cell in the nasal response to aspirin in aspirin-sensitive asthma.

BACKGROUND: A subset of patients with asthma experience adverse nasoocular reactions after ingestion of aspirin or agents that inhibit cyclooxygenase. Recent evidence has implicated the leukotrienes in the nasoocular reaction, but the cellular sources and mechanism of activation are unknown. We used nasal lavage with and without a 5-lipoxygenase inhibitor, zileuton, to define the role of leukotrienes and to profile nasal cellular activation during this reaction. METHODS: A group of eight patients with asthma shown to have adverse reactions to aspirin documented by a 15% or greater decrease in forced expiratory volume in 1 second, accompanied by an elevation in urinary leukotriene E4 after ingestion of aspirin, received aspirin or placebo in a study with a crossover design. Nasal symptoms and nasal tryptase, histamine, leukotriene, and eosinophil cationic protein levels were evaluated. Serum tryptase and urinary histamine levels were also assessed. Subjects were then randomized to receive a week of treatment with zileuton or placebo, according to a double-blind, crossover design followed by aspirin challenge and measurement of the same mediators. RESULTS: Aspirin ingestion produced a marked increase in nasal symptoms from a baseline symptom score of 2.1 +/- 0.7 to a maximum of 8.4 +/- 1.2 (p < 0.0007). Aspirin ingestion produced a mean maximal increase in nasal tryptase of 3.5 +/- 2.6 ng/ml, whereas placebo ingestion produced a mean maximal increase of 0.1 +/- 0.2 ng/ml (p < 0.05, aspirin vs placebo). Mean maximal nasal histamine increased 1.73 +/- 1.16 ng/ml versus 0.08 +/- 0.08 ng/ml from baseline (p < 0.05, aspirin vs placebo). Aspirin produced a mean maximal increase in nasal leukotriene value of 152 pg/ml versus a 16 pg/ml decrease after placebo ingestion (p < 0.05). Zileuton treatment blocked the increase in nasal symptoms after aspirin ingestion (maximum nasal symptom score of 1.6 +/- 0.6 with zileuton vs 5.5 +/- 0.9 with placebo [p < 0.0053]). It also blocked the rise in nasal tryptase (p = 0.011) and nasal leukotriene (p < 0.05) levels after aspirin ingestion. Zileuton treatment had no significant effect on the recovery of nasal histamine. CONCLUSION: The increase in nasal symptoms in aspirin-sensitive patients with asthma after aspirin ingestion is associated with increases in nasal tryptase, histamine, and cysteinyl leukotriene levels. This mediator profile is consistent with mast cell activation during the nasal response to aspirin and suggests that 5-lipoxygenase products are essential for the nasal response to aspirin.

Adult↗

PubMed1994

Decline of Haemophilus influenzae type b disease in a region of high risk: impact of passive and active immunization.

Haemophilus influenzae type b (Hib) is a major cause of serious childhood bacterial infections. Before 1989 Alaska Native infants in the Yukon Kuskokwim Delta (YKD) had the highest recorded Hib disease rate, 2960:100,000 in children less than 1 year of age with 6 to 35 (mean, 13) cases/year between 1980 and 1988. In July, 1989, Alaska Area Native Health Service initiated a passive immunization project in the YKD using bacterial polysaccharide immunoglobulin (BPIG) administered at 3-month intervals to prevent Hib infections in infants less than 13 months of age. On January 1, 1991, after licensure of Hib conjugate vaccines for infants, the program was modified to a passive-active strategy using BPIG at birth and PedvaxHIB at 2, 4 and 12 months of age. Between July 1, 1989, and December 31, 1990, 80% of YKD children less than 1 year of age received at least 1 dose of BPIG. During this period there were 7 Hib cases in this age group, but only 1 of the cases had received any BPIG. Between January 1, 1991, and December 31, 1992, 4 Hib cases occurred in 2 YKD children. During the combined period, July 1, 1989, to December 31, 1992, the incidence of Hib disease for infants less than 1 year of age was 302:100,000. A dramatic decrease in Hib disease was observed in this high incidence region concurrent with implementation of passive and passive-active immunization strategies.

Bacterial Outer Membrane Proteins↗