Biomedical subjects

C Chan

Publications and source records attributed to C Chan.

At least 181 records · Page 10Linked to original sources

PubMed1994

Thiopyrano[2,3,4-cd]indoles as 5-lipoxygenase inhibitors: synthesis, biological profile, and resolution of 2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy]-4,5 -dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]butanoic acid.

Leukotriene biosynthesis inhibitors have potential as new therapies for asthma and inflammatory diseases. The recently disclosed thiopyrano[2,3,4-cd]indole class of 5-lipoxygenase (5-LO) inhibitors has been investigated with particular emphasis on the side chain bearing the acidic functionality. The SAR studies have shown that the inclusion of a heteroatom (O or S) in conjunction with an alpha-ethyl substituted acid leads to inhibitors of improved potency. The most potent inhibitor prepared contains a 2-ethoxybutanoic acid side chain. This compound, 14d (2-[2-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methox y]- 4,5-dihydro-1H-thiopyrano[2,3,4-cd]indol-2-yl]ethoxy]-butanoic acid, L-699,333), inhibits 5-HPETE production by human 5-LO and LTB4 biosynthesis by human PMN leukocytes and human whole blood (IC50s of 22 nM, 7 nM and 3.8 microM, respectively). The racemic acid 14d has been shown to be functionally active in a rat pleurisy model (inhibition of LTB4, ED50 = 0.65 mg/kg, 6 h pretreatment) and in the hyperreactive rat model of antigen-induced dyspnea (50% inhibition at 2 and 4 h pretreatment; 0.5 mg/kg po). In addition, 14d shows excellent functional activity against antigen-induced bronchoconstriction in the conscious squirrel monkey [89% inhibition of the increase in RL and 68% inhibition in the decrease in Cdyn (0.1 mg/kg, n = 3)] and in the conscious sheep models of asthma (iv infusion at 2.5 micrograms/kg/min). Acid 14d is highly selective as an inhibitor of 5-LO activity when compared to the inhibition of human 15-LO, porcine 12-LO and ram seminal vesicle cyclooxygenase (IC50 > 5 microM) or competition in a FLAP binding assay (IC50 > 10 microM). Resolution of 14d affords 14g, the most potent diastereomer, which inhibits the 5-HPETE production of human 5-LO and LTB4 biosynthesis of human PMN leukocytes and human whole blood with IC50s of 8 nM, 4 nM, and 1 microM respectively. The in vitro and in vivo profile of 14d is comparable to that of MK-0591, which has showed biochemical efficacy in inhibiting ex vivo LTB4 biosynthesis and urinary LTE4 excretion in clinical trials.

Animals↗

PubMed1994

Determinants of bone mass in Chinese women aged 21-40 years. II. Pattern of dietary calcium intake and association with bone mineral density.

A study on the determinants of bone mass in young women is being carried out among 287 young Chinese women aged 21-40 years. The baseline cross-sectional data show that the mean dietary calcium intake, estimated from the quantitative food frequency method, was 448 mg/day (standard deviation = 219). About 50% of the calcium source was from vegetables and 22% from dairy products. Among women aged 21-30 years, those with a dietary calcium intake of at least 600 mg/day had a 4%-7% higher mean bone mineral density at the spine and femur when compared with those with a mean intake below 300 mg/day. In women aged 31-40 years, subjects belonging to the highest quartile of calcium density (> or = 35 mg/420 kJ) had a 3%-8% higher mean bone mineral density at the spine and femur when compared with those in the lowest quartile (< 20.8 mg/420 kJ). Favorable calcium intake is beneficial in this population of young women with habitual low dietary calcium intake.

Adult↗

PubMed1994

Expression of I mu-C gamma hybrid germline transcripts subsequent to immunoglobulin heavy chain class switching.

Germline CH transcripts initiate from a non-coding I exon and terminate downstream of the associated CH exons. Ig heavy chain class switch recombination from the VDJ-C mu gene to particular downstream CH genes appears to be regulated by a process that involves mitogen and/or cytokine induction of germline CH transcripts from the downstream genes. We have examined the expression of germline C mu transcripts (I mu-C mu transcripts) in splenic B cells and pre-B cell lines after cytokine and mitogen stimulation. In contrast to the expression of the germline transcripts from downstream CH genes, expression of germline C mu transcripts was constitutive and unaffected by mitogen and cytokine treatment. After a primary switch recombination event, the germline I mu promoter, which is now associated with a downstream CH gene, continues to be active--leading to the generation of a novel germline transcript consisting of the I mu exon spliced to the CH exons of the switched CH gene. We discuss the potential role of the expression of hybrid I mu-containing transcripts in the class switch process. We also describe a novel and sensitive assay, based on the detection of the hybrid I mu-containing transcripts, that allows detection of class switch recombination events even in heterogeneous populations of cells.

Animals↗

PubMed1994

Congenital cutis laxa with a dominant inheritance and early onset emphysema.

Two cases (mother and daughter) are reported of autosomal dominant cutis laxa which are unusual in being associated with early onset emphysema. Both mother and daughter have been smokers and are heterozygotes for the alpha 1 antitrypsin genotype. The combination of cigarette smoking and subnormal alpha 1 antitrypsin levels may explain the pulmonary spread in these two women who have what is usually a benign form of cutis laxa limited to the skin.

Adult↗

PubMed1994

Acute outcome of percutaneous Inoue-balloon mitral commissurotomy.

This study examines the acute results and the potential impact, if any, of 16 clinical, echocardiographic, hemodynamic and balloon-related variables on the acute outcomes of Inoue-balloon percutaneous transvenous mitral commissurotomy (PTMC). Of 107 patients, PTMC was successfully completed in 105 (98%) without cardioembolism or death, and resulted in an increase in mitral valve area from 0.8 +/- 0.2 cm2 to 1.7 +/- 0.4 cm2 (p = 0.0001) as assessed echocardiographically. Optimal results defined as a valve area improvement of > or = 50% and/or a final valve area of > or = 1.5 cm2 without significant mitral regurgitation (> or = 2 grade increase in mitral regurgitation or a final regurgitation > or = 3+) was obtained in 96 patients (91%). Significant mitral regurgitation was observed in six patients. On univariate analysis, patients with suboptimal results were older (52 +/- 7 vs. 44 +/- 10 years, p = 0.037) and were likely to have the procedure performed during the learning phase (first 33 vs.. subsequent 72 patients, p = 0.007) than those with optimal results, and patients with resultant significant mitral regurgitation had more severe pre-existing mitral regurgitation compared with those without (1.4 +/- 0.5 vs. 0.7 +/- 0.7, p = 0.0098). However, there were no independent predictors of either acute outcome identified in multivariate analysis. We therefore conclude that although Inoue-balloon PTMC is a safe and highly effective procedure with a low risk of creating severe mitral regurgitation, the acute outcomes cannot be accurately predicted.

Adult↗

PubMed1993

Inhibitors of cholesterol biosynthesis. 1. 3,5-Dihydroxy-7-(N-imidazolyl)-6-heptenoates and -heptanoates, a novel series of HMG-CoA reductase inhibitors.

3,5-Dihydroxy-7-(N-imidazolyl)heptanoates 4 and the corresponding heptenoates 5 were synthesized as novel classes of potent HMG-CoA reductase (HMGR) inhibitors in which members of the latter series possess enzyme inhibitory activity greater than that of lovastatin 1 and pravastatin 2. Structure-activity studies show that the 7-(N-imidazolyl)heptenoates 5 are more active than the corresponding heptanoates 4. For both imidazolyl series, the 4-fluorophenyl group is preferred at C-5, and a broad range of aryl substituents which promote widely different lipophilicities is tolerated at C-4. While the CF3 group is preferred at C-2 in the heptanoate series, the 2-(1-methylethyl) substituent is optimal in the heptenoate series. The 2-(1-methylethyl) and 5-(4-fluorophenyl) groups can be interchanged in the latter series as exemplified by 5ab. Enzyme inhibitory activity resides principally in the 3R,5S series. These potent HMGR inhibitory activities by members of the heptenoate series translated well into whole cell activities in HepG2 cells. X-ray crystallographic studies on the active enantiomer 28 reveal noncoplanarity of the heptenoate C-C double bond with the imidazole ring; this finding provides an explanation for the high acid stability of the heptenoate series.

Animals↗

PubMed1993

Substituted thiopyrano[2,3,4-c,d]indoles as potent, selective, and orally active inhibitors of 5-lipoxygenase. Synthesis and biological evaluation of L-691,816.

Thiopyrano[2,3,4-c,d]indoles are a new class of 5-lipoxygenase (5-LO) inhibitors. SAR studies have demonstrated that the thiopyran ring, the 5-phenylpyridine substituent, and an acidic functional group on a four-carbon C-2 side chain are all required for optimal inhibitor potency. In contrast, the indolic nitrogen may be substituted with a variety of lipophilic groups. As a result of the SAR investigation, 44 (L-691,816; 5-[3-[1-(4-chlorobenzyl)-4-methyl-6-[(5-phenylpyridin-2-yl)methoxy ]- 4,5-dihydro-1H-thiopyrano[2,3,4-c,d]indol-2-yl]-2,2-dimethylpro pyl]-1H- tetrazole) has been identified as a potent inhibitor of the 5-LO reaction both in vitro and in a range of in vivo models. Compound 44 inhibits 5-HPETE production by both rat and human 5-LO and LTB4 synthesis in human PMN leukocytes (IC50s 16, 75, and 10 nM, respectively). The mechanism of inhibition of 5-LO activity by compound 44 appears to involve the formation of a reversible deadend complex with the enzyme and does not involve reduction of the nonheme iron of 5-LO. Compound 44 is highly selective for 5-LO when compared to the inhibition of human FLAP, porcine 12-LO, and also ram seminal vesicle cyclooxygenase. In addition, 44 is orally active in a rat pleurisy model (inhibition of LTB4, ED50 = 1.9 mg/kg; 8 h pretreatment) as well as in the hyperreactive rat model of antigen-induced dyspnea (ED50 = 0.1 mg/kg; 2-h pretreatment). Excellent functional activity was also observed in both the conscious allergic monkey and sheep models of asthma. In the latter case, the functional activity observed correlated with the inhibition of urinary LTE4 excretion.

Administration, Oral↗

PubMed1993

Comparison of atovaquone (566C80) with trimethoprim-sulfamethoxazole to treat Pneumocystis carinii pneumonia in patients with AIDS.

BACKGROUND: Both trimethoprim-sulfamethoxazole and pentamidine are effective as treatments for Pneumocystis carinii pneumonia, but adverse effects frequently limit their use. Atovaquone (566C80) is a new hydroxynaphthoquinone with activity against P. carinii. METHODS: We conducted a double-blind, multicenter study in patients with the acquired immunodeficiency syndrome and mild or moderately severe P. carinii pneumonia. They were randomly assigned to 21 days of orally administered treatment three times daily with either atovaquone (750 mg) or trimethoprim (320 mg) plus sulfamethoxazole (1600 mg). RESULTS: Of the 322 patients with histologically confirmed P. carinii pneumonia, 160 received atovaquone and 162 received trimethoprim-sulfamethoxazole. Of those who could be evaluated for therapeutic efficacy, 28 of 138 patients given atovaquone (20 percent) and 10 of 146 patients given trimethoprim-sulfamethoxazole (7 percent) did not respond (P = 0.002). Treatment-limiting adverse effects required a change of therapy in 11 patients in the atovaquone group (7 percent) and 33 patients in the trimethoprim-sulfamethoxazole group (20 percent) (P = 0.001). Therapy involving only the initial drug was successful and free of adverse effects in 62 percent of those assigned to atovaquone and 64 percent of those assigned to trimethoprim-sulfamethoxazole. Within four weeks of the completion of treatment, there were 11 deaths in the atovaquone group (4 due to P. carinii pneumonia) and 1 death in the trimethoprim-sulfamethoxazole group (P = 0.003). Diarrhea at entry was associated with lower plasma drug concentrations (P = 0.009), therapeutic failure (P < 0.001), and death (P < 0.001) in the atovaquone group but not in the trimethoprim-sulfamethoxazole group. CONCLUSIONS: For the treatment of P. carinii pneumonia, atovaquone is less effective than trimethoprim-sulfamethoxazole, but it has fewer treatment-limiting adverse effects.

AIDS-Related Opportunistic Infections↗

PubMed1993

Stimulatory effect of TGF-beta on anionic glycoconjugate synthesis by rat calvarial cells: specificity, uncoupling of cell density dependence, and modulation by chondroitin sulfate.

Anchorage-dependent cultures of a population of cells derived from the outer part of the rat calvaria demonstrated decreased net accumulation of radiolabeled chondroitin sulfate (CS) and hyaluronic acid (HA) per cell as the cell density of the cultures increased. The addition of TGF-beta 1 resulted in large stimulations of the net CS, but not of the net HA, accumulating in the medium at all cell densities and an abolition of the density-dependent effect. These effects were largely due to increases in newly synthesized CS appearing in the medium. Supplementation of the culture media with CS had complex but relatively small effects on the stimulation of the net accumulation of radiolabeled medium CS by TGF-beta 1. The addition of TGF-beta 1 also resulted in a biphasic effect on cell growth that depended on the plating density, but cell growth differences could not account for the marked stimulation of CS synthesis by TGF-beta 1. Experiments with cycloheximide and beta-xyloside and isolation of the intact anionic glycoconjugates (AG) indicated that although synthesis of core protein was the limiting factor in CS synthesis, TGF-beta 1 stimulated the synthesis of CS chain when sufficient beta-xyloside acceptor was available. The overall results suggest that, in this cell system, the action of TGF-beta 1 on the synthesis of the major extracellular AGs is characterized by a relatively specific upregulation of CS proteoglycan (PG) synthesis and an uncoupling of the inhibitory effect of high cell density on CS PG synthesis.

Animals↗

PubMed1993

Assessment of the in vivo biochemical efficacy of orally active leukotriene biosynthesis inhibitors.

In man, the therapeutic effectiveness of specific inhibitors of leukotriene (LT) biosynthesis against allergen-induced bronchoconstriction appears to be related to the in vivo biochemical efficacy of these compounds, as measured by inhibition of whole blood LTB4 generation (upon A23187 stimulus) and, particularly, urinary LTE4 excretion. Accordingly, we have assessed the ability of two clinically documented LT biosynthesis inhibitors, zileuton and MK-886, and the structurally novel 5-lipoxygenase activating protein antagonist, MK-0591, to inhibit the production of these inflammatory arachidonic acid metabolites in laboratory dogs. Zileuton (2 mg/kg) was extremely bioavailable in dogs (> 10 microM plasma concentrations), and inhibited the A23187-induced ex vivo production of LTB4 by venous blood by > 90%, in concordance with its potency in canine blood in vitro (IC50 = 1.1 microM). Despite this degree of inhibition in whole blood, urinary LTE4 excretion was reduced by only 52%, a profile of activity similar to that seen in clinical studies. MK-886 was less well absorbed, with plasma concentrations of 3 microM being achieved only at 25 mg/kg. These levels resulted in < 45% inhibition of LTB4 production, but a significant (p < 0.05) 47% inhibition of urinary LTE4 excretion. MK-0591 was similarly bioavailable (compared with MK-886), but 10-fold more active in vivo as a 2 mg/kg dose resulted in 41-62% inhibition of urinary LTE4 excretion (p < 0.05 vs controls; n = 4, 28). Significant inhibition of ex vivo LTB4 synthesis was also observed at this dose (49%), in accord with peak plasma concentrations of 0.5 microM and an in vitro potency of 0.2-0.4 microM (IC50) in whole blood from these animals. At higher dose (10 mg/kg), MK-0591 inhibited LTE4 excretion by 69%, with 88% inhibition of the LT biosynthetic capacity of whole blood. These data demonstrate that the biochemical efficacy of structurally diverse leukotriene biosynthesis inhibitors can be assessed in vivo in normal laboratory dogs. Such measurements, combined with bioavailability data from other species, may be useful for predicting biochemical activity in man.

Animals↗

PubMed1993

Progressive decrease in myocardial ischemia assessed by intracoronary electrocardiogram during successive and prolonged coronary occlusions in angioplasty.

Progressive decrease in chest pain and surface ECG changes are commonly observed during successive balloon inflations in coronary angioplasty, which suggests a decrease in myocardial ischemic response. To assess this hypothesis, we continuously recorded intracoronary ECGs during four balloon inflations; each of the inflations was maintained to a minimum of 120 seconds in 19 patients who had significant stenosis in the left anterior descending artery and normal left ventricular function. Three successive QRS-T complexes were analyzed on surface and intracoronary ECGs for measurements of ST-segment elevation 60 milliseconds after the J point. Surface ECG changes were compared with intracoronary ECG changes. On intracoronary ECG, ST area (in square millimeters) and T wave amplitude (in millimeters) were also computed. Chest pain was noted as present or absent during each successive balloon inflation. Ability of intracoronary ECG to detect myocardial ischemia, which was defined as ST-segment elevation greater than 1 mm during balloon inflations 1 to 4, was 89%, 89%, 84%, and 74%, respectively and was higher than that of surface ECG, which was 68%, 63%, 68%, and 58%, respectively. On intracoronary ECG, when compared with the first balloon inflation, a significantly smaller increase in ST-segment elevation was noted during each subsequent balloon inflation, whereas a significantly smaller increase in ST area and T wave amplitude was noted only during balloon inflation 4. The number of patients who experienced chest pain decreased from 15 to 13, 10 and 6 from the first to the fourth balloon inflation. This report demonstrates a progressive decrease in myocardial ischemic response during successive and prolonged balloon occlusions.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1993

A longitudinal study of the determinants of bone mass in Chinese women aged 21 to 40. I. Baseline association of anthropometric measurements with bone mineral density.

The bone mineral density of the lumbar spine (L2 to L4) and neck of the femur of 293 Chinese women aged 21 to 40 years was measured using a dual x-ray densitometer. The participants were recruited from subjects registered with the University Family Medicine Clinic in Hong Kong. Our cross-sectional data showed that maximal bone mass occurs in the early 30s. Both the spine and hip bone masses were observed to decline at a rate of around 1% per annum from the early 30s onward. Body weight, lean body mass, and body fatness were significantly associated with the mineral density of the spinal and femoral bones after or around the attainment of peak bone mass, while no correlation of these data was observed in the younger age group (20 to 28 years). Other factors may play a more important role than body mass in influencing bone mineral density before attainment of peak bone mass.

Absorptiometry, Photon↗

PubMed1993

Ayurvedic agents produce differential effects on murine and human melanoma cells in vitro.

This study was performed to evaluate the relative efficacy of Maharishi Amrit Kalash ambrosia (MAK-5) and Maharishi Amrit Kalash nectar (MAK-4) on murine (B-16) and human (SK-Mel) melanoma cells in culture. Ethanol extract (EE) of MAK-5 (EE-MAK-5) induced morphological differentiation (enlargement of soma and nuclei and formation of long dendritic processes) and growth inhibition in mouse melanoma cells, whereas EE-MAK-5 inhibited only growth in human melanoma cells. Murine melanoma cells were more sensitive (about 3 times) than human melanoma cells in culture to EE-MAK-5; the aqueous extract (AE) of MAK-5 (AE-MAK-5) was ineffective in both cells. Boiling EE-MAK-5 for 10 minutes or exposing it to light at room temperature for 72 hours did not alter growth-inhibiting potency. Ethanol extract of another herbal agent, MAK-4 (EE-MAK-4), inhibited growth in human melanoma cells but not in mouse melanoma cells. AE-MAK-4 was ineffective for both cells. These results suggest that murine and human melanoma cells respond differently to MAK-5 and MAK-4 and that human melanoma growth-inhibiting agents are present in both EE-MAK-5 and EE-MAK-4.

Animals↗

PubMed1993

NDC1: a nuclear periphery component required for yeast spindle pole body duplication.

The spindle pole body (SPB) of Saccharomyces cerevisiae serves as the centrosome in this organism, undergoing duplication early in the cell cycle to generate the two poles of the mitotic spindle. The conditional lethal mutation ndc1-1 has previously been shown to cause asymmetric segregation, wherein all the chromosomes go to one pole of the mitotic spindle (Thomas, J. H., and D. Botstein. 1986. Cell. 44:65-76). Examination by electron microscopy of mutant cells subjected to the nonpermissive temperature reveals a defect in SPB duplication. Although duplication is seen to occur, the nascent SPB fails to undergo insertion into the nuclear envelope. The parental SPB remains functional, organizing a monopolar spindle to which all the chromosomes are presumably attached. Order-of-function experiments reveal that the NDC1 function is required in G1 after alpha-factor arrest but before the arrest caused by cdc34. Molecular analysis shows that the NDC1 gene is essential and that it encodes a 656 amino acid protein (74 kD) with six or seven putative transmembrane domains. This evidence for membrane association is further supported by immunofluorescent localization of the NDC1 product to the vicinity of the nuclear envelope. These findings suggest that the NDC1 protein acts within the nuclear envelope to mediate insertion of the nascent SPB.

Amino Acid Sequence↗

PubMed1993

Results of balloon aortic valvuloplasty in patients with aortic stenosis associated with significant aortic regurgitation.

The influence of balloon aortic valvuloplasty (BAV) on aortic regurgitation (AR) in patients with severe aortic stenosis associated with greater than or equal to grade II AR was studied by supraaortic angiogram before and after BAV. The results of 50 patients aged 72 +/- 12 years with significant AR before BAV (group A) were compared to 297 patients (mean age 76 +/- 10 years) with no or mild AR (group B). In group A, the patients had a higher left ventricular end diastolic volume (96 +/- 19 mL/m 2 vs 81 +/- 32 mL/m 2, P less than 0.01) and left ventricular end diastolic pressure (23 +/- 9 mmHg vs 19 +/- 9 mmHg, P less than 0.01). The aortic valve area was similar in both groups. Following BAV, the improvement in aortic valve area and hemodynamics were similar in both groups. In group A, AR remained unchanged in 31 patients (62%), increased by 1 grade in 13 patients (26%), and decreased by 1 grade in 6 patients (12%). In group B, AR increased by greater than 1 grade in 34 patients (11%) and greater than 2 grades in 4 patients (1.3%) post-BAV. Two patients in group B underwent emergency aortic valve replacement following BAV because of severe acute AR. In conclusion, when it is indicated, BAV can be performed with similar risk in patients with significant AR.

Aged↗

PubMed1993

Leukemia inhibitory factor expression in human carotid plaques: possible mechanism for inhibition of large vessel endothelial regrowth.

One common feature of atherosclerotic plaques is the denudation of the endothelium covering the plaque and subsequent failure of endothelial regrowth in contrast to a marked proliferation of neocapillaries arising from the vasa vasorum within the medial wall. Previous studies in vitro have demonstrated the ability of leukemia inhibitory factor (LIF) to potently inhibit aortic endothelial cell growth while only slightly inhibiting the growth of adrenal cortex capillary endothelial cells. This selective effect of LIF on endothelial cells from different sources suggests that it may play a role in the failure of endothelial regrowth in atherosclerosis. Sections of human carotid endarterectomy samples were examined by in situ hybridization for LIF mRNA expression. In one-third of the samples (4/12) examined, cells within the atherosclerotic plaque exhibited LIF expression. Immunohistochemistry of serial sections suggested that the LIF-positive cells were activated macrophages. These results suggest that LIF may play a role in the pathogenesis of atherosclerosis, particularly the denudation of the large vessel endothelium.

Arteriosclerosis↗

PubMed1993

Selective splenocaval shunt for bleeding portal hypertension: fifteen-year evaluation period.

BACKGROUND: Splenocaval shunts have been used in this hospital since 1974 as an alternative to the distal splenorenal shunt. This report will detail the long-term results with this operation. METHODS: Thirty-three patients who were subjected to selective splenocaval shunts for treatment of hemorrhagic portal hypertension are reported. Mean age was 48.4 years. Twenty patients were women. Twenty-seven patients were in Child class A and six were in Child class B. RESULTS: There were five postoperative deaths. Two patients experienced rebleeding. One patient had shunt obstruction and one patient had severe clinical encephalopathy. Actuarial survival rate was 54.9% at 5 years and was 47.5% at 15 years. At the time of evaluation 12 patients were alive and well (shortest observation period, 2 months and longest observation period, 173 months). One of these patients has mild encephalopathy. CONCLUSIONS: Selective splenocaval shunts are a good alternative for treatment of hemorrhagic portal hypertension in patients with good liver function.

Actuarial Analysis↗

PubMed1992

Quantitation of eosinophil Major Basic Protein cytotoxicity to rodent respiratory epithelium.

Eosinophil Major Basic Protein (MBP) may be a potent effector in damaging airway epithelium and inducing acute (2-3 h) hyperresponsiveness to agonists in primates. Accordingly, interactions between human eosinophil MBP and guinea-pig airway epithelium were quantitated biochemically. MBP was extracted from human eosinophils and purified by size-exclusion HPLC. This resulted in a single protein band on electrophoresis, which cross-reacted with antisera raised to peptides derived from the predicted sequence of human MBP. This human MBP caused modest, but statistically significant, damage to respiratory epithelium (16.4% increase in efflux of 51Cr from guinea-pig tracheal rings) after 3 h of incubation with 10(-4) M concentration, but not with lower concentrations. These data demonstrates that MBP cytotoxicity to intact epithelium can be rapidly measured in vitro, and suggests that rodent airway epithelium may be relatively resistant to the cytotoxic effects of MBP.

Animals↗