Clinical immunology review series: An approach to the management of pulmonary disease in primary antibody deficiency.

The sinopulmonary tract is the major site of infection in patients with primary antibody deficiency syndromes, and structural lung damage arising from repeated sepsis is a major determinant of morbidity and mortality. Patients with common variable immunodeficiency may, in addition, develop inflammatory lung disease, often associated with multi-system granulomatous disease. This review discusses the presentation and management of lung disease in patients with primary antibody deficiency.

Cytokine induction of cytosolic phospholipase A2 and cyclooxygenase-2 mRNA is suppressed by glucocorticoids in human epithelial cells.

Prostaglandin (PG) release, which is increased in vivo by inflammatory conditions and in vitro by pro-inflammatory cytokines, is decreased by glucocorticoids. Two phospholipase A2 isoforms, secretory (sPLA2) and cytosolic (cPLA2,), have been implicated in inflammation. These enzymes catalyse the release of arachidonic acid which is then converted to prostaglandins by the cyclooxygenases (COX-1 and COX-2). Regulation of these events at the mRNA level is poorly characterised in epithelial cells. We have used a human epithelial-like cell line (A549) as a model system to study mRNA expression of sPLA2, cPLA2, COX-1 and COX-2. Following treatment of cells and extraction of RNA, semi-quantitative reverse transcription polymerase chain reaction (RT-PCR) was used to examine expression of these genes. We show a coordinate induction of both cPLA2 and COX-2 mRNA by pro-inflammatory cytokines which correlated with increased PGE2 release. By contrast, sPLA2 mRNA was undetectable and COX-1 was found to be expressed at a constant low level. In addition dexamethasone pretreatment significantly reduced both cPLA2 and COX-2 mRNA levels as well as PGE2 release following cytokine stimulation. These data indicate a major role for control of prostaglandin synthesis at the mRNA level of key synthetic genes in epithelial cells. Furthermore we show that a major mechanism of glucocorticoid action in preventing prostaglandin release occurs by suppression of cPLA2 and COX-2 mRNA levels.

Antibiotic restriction policies in public hospitals.

We surveyed annual expenditure on antimicrobial agents and the use of antimicrobial restriction policies. Restriction policies were in use in 25 of 27 of the hospitals surveyed. Restrictions on the use of antimicrobials were extended into specialty intensive care or haematology units in only 13 of 20 hospitals which had such units. Antimicrobial restriction policies were, for the most part, similar amongst the hospitals surveyed. Use of restriction policies within specialist units was associated with reduced total hospital antibiotic expenditure per bed per year.

Use of a chronic disease management programme in COPD to reduce hospital admissions.

Chronic obstructive pulmonary disease (COPD) accounts for a large number of hospital admissions and numerous interventions have attempted to reduce exacerbations requiring hospitalization. This paper describes the implementation of a community based COPD management programme led by a respiratory physiotherapist to improve home management of COPD and its effect on reducing readmissions and/or length of stay in hospital. One-hundred and twenty-five patients (median age 73) referred with COPD exacerbations met the criteria for the service; 95 received the intervention and data were available for 80. Median FEV1 was 0.86 L. Admission data, length of stay and total hospitalization days with COPD were compared for one year before and after the intervention. Overall there was no reduction in length of stay, admission frequency, or adjusted total hospitalization days with COPD, but median time interval to next exacerbation increased by 29%. In those who had had previous admissions (mean FEV1 0.58 L) total hospitalization days fell by 27%, length of stay fell by 58% despite an increase in admission frequency from one to two per year, and there was no change in median time interval to next hospitalized exacerbation. In our patients implementation of a Chronic Disease Management programme increased the time to next hospitalized exacerbation. Benefit was seen in the more severe patients however, with a significant reduction in both length of stay and total hospitalization days.

Pneumocystis carinii pneumonia as a complication of methotrexate treatment of asthma.

A 32 year old man with chronic severe asthma, requiring maintenance oral corticosteroids, was started on a weekly dose of methotrexate. Eleven weeks later he developed Pneumocystis carinii pneumonia. In the two years following treatment there has been no recurrence while oral corticosteroid treatment has been continued. Pneumocystis pneumonia should be considered in asthmatic patients taking methotrexate who present with fever, pulmonary infiltrates, and hypoxia.

Intravenous magnesium sulfate in acute, life-threatening asthma.

Magnesium, a physiologic calcium antagonist, is known to have a direct effect on calcium uptake in smooth muscle, resulting in smooth muscle relaxation. Studies of magnesium sulfate infusions in patients with mild or moderate-to-severe acute asthma have shown that it may have a significant bronchodilatory effect, similar to that of salbutamol (albuterol). We present the case of a patient with acute severe life-threatening asthma (initially in cardiorespiratory arrest) who responded to an IV infusion of magnesium sulfate after aggressive pharmacologic management failed to result in clinical improvement.

Drugs affecting the leukotriene pathway in asthma.

Drugs affecting the leukotriene pathway are emerging as a new class of asthma treatment--the first for more than 20 years. Development of these leukotriene antagonists should lead to greater understanding of the underlying processes in asthma and may result in a safe, oral, anti-asthmatic drug to benefit particular groups of asthmatic patients.

Evidence for involvement of NF-kappaB in the transcriptional control of COX-2 gene expression by IL-1beta.

The cyclooxygenase (COX) isoforms COX-1 and COX-2 convert arachidonic acid to prostaglandin (PG) precursors and are a limiting step in PG production. Interleukin-1beta (IL-1beta) treatment of type II A549 cells increases PGE2 synthesis via transcription- and translation-dependent induction of COX-2. IL-1beta produces a 10-fold induction of COX-2 mRNA and an 8-fold increase in COX-2 transcription that was temporally preceded by activation of the transcription factor nuclear factor-kappaB (NF-kappaB). The protein-tyrosine phosphatase inhibitor phenylarsine oxide (PAO) prevented both NF-kappaB activation and induction of COX-2 mRNA. We show that two putative NF-kappaB motifs, kappaBu (-447/-438) and kappaBd (-224/-214), from the COX-2 promoter bind p50/p65 NF-kappaB heterodimers in an IL-1beta-dependent manner and that the upstream element has the greater affinity. Finally, we demonstrate that the two NF-kappaB subunits, p50 and p65, synergistically activate a -917/+49 COX-2 promoter construct. We conclude that IL-1beta stimulates PG production via transcriptional activation of COX-2 and provide evidence that this may involve NF-kappaB.

Eicosanoid mediator expression in mononuclear and polymorphonuclear cells in normal subjects and patients with atopic asthma and cystic fibrosis.

BACKGROUND: Eicosanoids such as leukotrienes, prostaglandins, lipoxins, and 15-hydroperoxyeicosatetraenoic acid (15-HETE) cause bronchoconstriction, increased microvascular permeability, mucus secretion, and polymorph chemotaxis. These pro-inflammatory effects are important in diseases such as asthma and cystic fibrosis where the levels of mediators are increased both in the stable and acute state. A study was conducted to examine the expression of the mRNA for the enzymes of the eicosanoid pathways (5-lipoxygenase (5-LO), 5-lipoxygenase activating protein (FLAP), cyclo-oxygenases 1 and 2 (COX-1, COX-2), and 15-lipoxygenase (15-LO)) in normal subjects and in patients with stable atopic asthma and stable cystic fibrosis. METHODS: Reverse transcription polymerase chain reaction (RT-PCR) was used to examine the expression of total RNA for 5-LO, FLAP, COX-1, COX-2, and 15-LO in peripheral blood polymorphonuclear cells and mononuclear cells from the three subjects groups. RESULTS: The expression of mRNA for 5-LO and FLAP was similar in normal subjects and in patients with asthma and cystic fibrosis. COX-1 was increased in both cell types in asthmatic patients. COX-2 and 15-LO were increased in polymorphs of patients with atopic asthma but not in mononuclear cells. COX-2 and 15-LO were undetectable in either cell type in patients with cystic fibrosis whereas COX-1 levels in polymorphs were similar to those in patients with asthma. CONCLUSIONS: The increased leukotriene production in asthma and cystic fibrosis is not explained by an increase in transcription of 5-LO and FLAP. Transcription of 15-LO and COX-2 is increased in atopic asthma. Transcription of COX-1 is increased in both atopic asthma and cystic fibrosis.

Repression of cyclooxygenase-2 and prostaglandin E2 release by dexamethasone occurs by transcriptional and post-transcriptional mechanisms involving loss of polyadenylated mRNA.

The two cyclooxygenase (COX) isoforms convert arachidonic acid to precursor prostaglandins (PGs). Up-regulation of COX-2 is responsible for increased PG production in inflammation and is antagonized by corticosteriods such as dexamethasone. In human pulmonary A549 cells, interleukin-1beta (IL-1beta) increases prostaglandin E2 (PGE2) synthesis via dexamethasone-sensitive induction of COX-2. Nuclear run-off assays showed that COX-2 transcription rate was repressed 25-40% by dexamethasone, while PGE2 release, COX activity, and COX-2 protein were totally repressed. At the mRNA level, complete repression of COX-2 was only observed at later (6 h) time points. Preinduced COX-2 mRNA was also potently repressed by dexamethasone, yet suppression of transcription by actinomycin D showed little effect. This dexamethasone-dependent repression involved a reduced COX-2 mRNA half-life, was blocked by actinomycin D or cycloheximide, and was antagonized by the steroid antagonist RU38486. Repression of IL-1beta-induced PGE2 release, COX activity, and COX-2 protein by actinomycin D was only effective within the first hour following IL-1beta treatment, while dexamethasone was effective when added up to 10 h later, suggesting a functional role for post-transcriptional mechanisms of repression. Following dexamethasone treatment, shortening of the average length of COX-2 mRNA poly(A) tails was observed. Finally, ligation of the COX-2 3'-UTR to a heterologous reporter failed to confer dexamethasone sensitivity. In conclusion, these data indicate a major role for post-transcriptional mechanisms in the dexamethasone-dependent repression of COX-2 that require de novo glucocorticoid receptor-dependent transcription and translation. This mechanism involves shortening of the COX-2 poly(A) tail and requires determinants other than just the 3'-UTR for specificity.

Effect of the platelet-activating factor antagonist UK-74,505 on the early and late response to allergen.

The effect of UK-74,505, a specific platelet-activating factor (PAF) antagonist, on the early (EAR) and late asthmatic response (LAR) to inhaled allergen was studied in a randomized, double-blind, placebo-controlled crossover study. A total of eight adult male atopic asthmatic subjects completed the protocol (one withdrew after screening), all having demonstrated a dual response to inhaled allergen (EAR, > 20% fall in FEV1 between 0 and 1 h; LAR, > 15% fall in FEV1 between 4 and 8 h after challenge). Subjects were studied on 2 days at least 10 days apart. After measurement of baseline FEV1, subjects ingested a single oral dose of 100 mg UK-74,505 or matched placebo (P). Allergen challenge was performed 3 h later and the FEV1 was then measured for 8 h. There was no difference between UK-74,505 and placebo in the maximum percentage change from baseline (+/- SEM) for either EAR or LAR (EAR, UK-74,505 -25.6 +/- 4.8%, P -24.0 +/- 3.3%; LAR, UK-74,505 -20.8 +/- 4.4%, P -25.7 +/- 3.8%). There was no significant difference in the area under the percentage change from baseline FEV1-time curve. Ex vivo platelet aggregation to PAF was measured at 0, 2, 6, 8, and 10 h after the dose. There was marked inhibition of platelet aggregation to PAF for 10 h following UK-74,505 but not placebo (% maximum aggregation to PAF, UK-74,505, -69.9%; P, 0.13%; p = 0.0001). Histamine challenge was performed in five patients the day before and after each study day. There was no significant difference between UK-74,505 and placebo in PD20 to histamine (mean PD20 before and after UK-74,505, 1.31 and 0.96 mumol; P, 1.32 and 1.17 mumol). UK-74,505 did not affect either the EAR or the LAR to inhaled allergen or bronchial responsiveness, despite its potency and long duration of action. This suggests that PAF does not have a major role in the acute response to inhaled allergen.

Effect of a novel potent platelet-activating factor antagonist, modipafant, in clinical asthma.

Platelet-activating factor (PAF), proposed as an important inflammatory mediator in asthma, reproduces several of the features of asthma, such as microvascular leakage, mucus secretion, bronchoconstriction, and possibly increased airway responsiveness. Modipafant (UK-80,067) is the (+)-enantiomer of UK-74,505, a potent and specific PAF antagonist. We have assessed the effect of modipafant over 28 d in adult subjects with moderately severe asthma in a placebo-controlled parallel group study. A total of 218 patients with asthma were enrolled into the single-blind run-in, of whom 120 (93 males and 27 females, mean age 41.0 yr) entered the double-blind treatment phase after demonstrating symptomatic asthma in the final week of the single-blind run-in phase. Patients could take up to 1600 micrograms inhaled corticosteroid and an inhaled beta 2 agonist as rescue medication. A total of 59 patients with asthma took modipafant (one 50 mg capsule twice daily), and 61 took matched placebo. There was no significant difference between placebo and modipafant in diurnal variation in PEF, morning and evening PEF, clinic FEV1, rescue bronchodilator usage, symptom score, or airway responsiveness. We previously showed that the racemate UK-74,505 had no effect on antigen challenge, and this study shows that the active (+)-enantiomer modipafant has no effect in chronic asthma. This suggests that PAF is not an important mediator in asthma.