Allergic bronchopulmonary aspergillosis: new concepts of pathogenesis and treatment

Allergic bronchopulmonary aspergillosis (ABPA) is a condition that results from a hypersensitivity reaction to the fungus Aspergillus fumigatus. The purpose of the present review is to examine the pathogenesis of this condition and the evidence for treatments available. Allergic bronchopulmonary aspergillosis is characterized by an intense airway inflammation with eosinophils and the formation of mucus plugs. Clinically, there are periods of exacerbation and remission that may lead to proximal bronchiectasis and fibrotic lung disease. New evidence confirms the role of intense airway inflammation with eosinophils, but also suggests a role for interleukin (IL)-8/neutrophil-mediated inflammation in this process, and the potential deficiency of anti-inflammatory cytokines such as reduced IL-10. Treatment for ABPA has so far focused on corticosteroids to suppress eosinophilic airway inflammation. An expanding knowledge of the pathology of ABPA also suggests other therapies may be of potential benefit, particularly the use of azole antifungal agents. Allergic bronchopulmonary aspergillosis is itself an important complication of asthma and cystic fibrosis. A greater understanding of the condition is required to improve management and well-designed clinical trials need to be carried out to critically assess new and current treatments. In addition, the information gained from the studies of its pathogenesis has the potential to benefit our understanding of the disease processes in asthma and bronchiectasis.     

Mice lacking angiotensin-converting enzyme have increased energy expenditure, with reduced fat mass and improved glucose clearance

In addition to its role in the storage of fat, adipose tissue acts as an endocrine organ, and it contains a functional renin-angiotensin system (RAS). Angiotensin-converting enzyme (ACE) plays a key role in the RAS by converting angiotensin I to the bioactive peptide angiotensin II (Ang II). In the present study, the effect of targeting the RAS in body energy homeostasis and glucose tolerance was determined in homozygous mice in which the gene for ACE had been deleted (ACE(-/-)) and compared with wild-type littermates. Compared with wild-type littermates, ACE(-/-) mice had lower body weight and a lower proportion of body fat, especially in the abdomen. ACE(-/-) mice had greater fed-state total energy expenditure (TEE) and resting energy expenditure (REE) than wild-type littermates. There were pronounced increases in gene expression of enzymes related to lipolysis and fatty acid oxidation (lipoprotein lipase, carnitine palmitoyl transferase, long-chain acetyl CoA dehydrogenase) in the liver of ACE(-/-) mice and also lower plasma leptin. In contrast, no differences were detected in daily food intake, activity, fed-state plasma lipids, or proportion of fat excreted in fecal matter. In conclusion, the reduction in ACE activity is associated with a decreased accumulation of body fat, especially in abdominal fat depots. The decreased body fat in ACE(-/-) mice is independent of food intake and appears to be due to a high energy expenditure related to increased metabolism of fatty acids in the liver, with the additional effect of increased glucose tolerance.     

Compressive and shear force generated in the lumbar spine of female rowers

Rowers have and accrue greater lumbar spine bone mineral density (BMD) associated with mechanical loading produced during rowing. The aim of this study was to estimate the mechanical loading generated at the lumbar spine (LS) that is apparently providing an osteogenic benefit. The cohort comprised 14 female rowers (average age: 19.7yrs; height: 170.9 cm, weight: 59.5 kg) and 14 female matched controls (average age: 20.9 m yrs; height: 167.5 cm; weight: 58.1 kg). BMD was assessed using the Hologic QDR 2000+ bone densitometer, indicating higher lumbar spine BMD in the rowers compared to the control subjects (1,069 +/- 0.1 vs. 1,027 +/- 0.1 g/cm2). No significant difference existed for BMD at any other site. All rowers performed a six-minute simulated race on a Concept II rowing ergometer. Mechanical loading generated at the lumbar spine during this task was assessed using a two-dimensional model of the spine, enabling the calculation of the compressive and shear forces at L4/L5. The shear force was the joint reaction force perpendicular to the spine at the L4/L5 joint. Peak compressive and shear force at the lumbar spine of the rowers were 2,694 +/- 609 (N) and 660 +/- 117 (N), respectively. Peak compressive force at the LS relative to body weight was 4.6 times body weight. The literature would suggest that forces of this magnitude, generated at the LS during maximal rowing, may be contributing to the site specific higher LS BMD found in the rowers.     

Acute and Subacute Changes in the Ultrasound Measurements of the Calcaneus Following Intense Exercise

The amount of exercise necessary to cause bone structural change in humans is unknown. We examined whether a single bout of intense exercise in vivo leads to acute and subacute changes in the physical properties of bone as measured by ultrasound. It was hypothesized that structural changes such as accumulation of fatigue microdamage would result in a decrease in velocity of sound (VOS) and broadband ultrasound attenuation (BUA) across the calcaneus. We performed a prospective cohort study in 111 (97 M, 14 F) entrants of the 1996 Melbourne marathon (42.3 km) and 28 (10 M, 18 F) nonrunning controls. Runners had a mean (SD) age of 45.3 ± 11.4 years (range 20–75), had completed 15.2 ± 17.3 prior marathons (0–88), and had been running regularly for 14.2 ± 9.2 years (0.25–50). An ultrasound densitometer (Cuba Clinical, McCue) was used to measure VOS and BUA across the right calcaneus. Runners were tested on three occasions: 1-3 days prior to, immediately after (<2 hours), and 5-6 days following the marathon. Seventy-three (66%) runners presented for all three measurements. Controls were tested on three occasions with the same time intervals as the runners. BUA values in the runners were significantly elevated by 5.0% immediately after the marathon but returned to baseline levels by the third test session (P= 0.0001). Changes in BUA values in the controls were not significant and all were less than 0.7% (P= 0.88). Age was a significant independent predictor of the BUA change between test 1 and test 2 in the runners (β= 0.2094; SE = 0.0917; P= 0.03). VOS measurements were not significantly different across the three testing sessions in both the runners (P= 0.07) and the controls (P= 0.33). Therefore, ultrasound measurements of BUA and VOS did not detect evidence of lasting structural change in the calcaneus following a marathon. Received: 15 July 1997 / Accepted: 11 May 1998     

Determinants of bone density in 30- to 65-year-old women: a co-twin study.

Reported effects of body composition and lifestyle on bone mineral density in pre-elderly adult women have been inconsistent. In a co-twin study, we measured bone mineral density, lean and fat mass, and lifestyle factors. Analyzing within pair differences, we found negative associations between bone mineral density and tobacco use (2.3-3.3% per 10 pack-years) and positive associations with sporting activity and lean and fat mass. INTRODUCTION: Reported effects of body composition and lifestyle of bone mineral density in pre-elderly adult women have been inconsistent. METHODS: In a co-twin study of 146 female twin pairs aged 30 to 65 years, DXA was used to measure bone mineral density at the lumbar spine, total hip, and forearm, total body bone mineral content, and lean and fat mass. Height and weight were measured. Menopausal status, dietary calcium intake, physical activity, current tobacco use, and alcohol consumption were determined by questionnaire. Within-pair differences in bone measures were regressed through the origin against within-pair differences in putative determinants. RESULTS: Lean mass and fat mass were associated with greater bone mass at all sites. A discordance of 10 pack-years smoking was related to a 2.3-3.3% (SE, 0.8-1.0) decrease in bone density at all sites except the forearm, with the effects more evident in postmenopausal women. In all women, a 0.8% (SE, 0.3) difference in hip bone mineral density was associated with each hour per week difference in sporting activity, with effects more evident in premenopausal women. Daily dietary calcium intake was related to total body bone mineral content and forearm bone mineral density (1.4 +/- 0.7% increase for every 1000 mg). Lifetime alcohol consumption and walking were not consistently related to bone mass. CONCLUSION: Several lifestyle and dietary factors, in particular tobacco use, were related to bone mineral density. Effect sizes varied by site. Characterization of determinants of bone mineral density in midlife and thereafter may lead to interventions that could minimize postmenopausal bone loss and reduce osteoporotic fracture risk.     

Induced sputum IL-8 gene expression, neutrophil influx and MMP-9 in allergic bronchopulmonary aspergillosis.

Allergic bronchopulmonary aspergillosis (ABPA) is a hypersensitivity reaction to the fungus Aspergillus fumigatus, causing severe asthma that may progress to bronchiectasis. Sputum neutrophilia can occur in association with sputum eosinophilia and correlates with the degree of bronchiectasis. The mechanisms of sputum neutrophilia in ABPA are not known. The aim of this study was to investigate the role of the chemokine interleukin (IL)-8 in sputum neutrophilia in ABPA. Induced sputum was obtained from subjects with ABPA (n=29), and compared to nonsensitised asthma (n=9) and healthy controls (n=21). Semiquantitative polymerase chain reaction was used to assess IL-8 gene expression in induced sputum and IL-8 protein was measured by enzyme-linked immunosorbent assay. Sputum IL-8 protein was significantly higher in ABPA compared to asthma and controls. IL-8 messenger ribonucleic acid/glyceraldehyde-3-phosphate dehydrogenase ratio was elevated in ABPA compared to asthma and controls. Sputum IL-8 correlated with sputum neutrophils, matrix metalloproteinase-9 levels and forced expiratory volume in one second. Interleukin-8 gene expression and protein release were increased in allergic bronchopulmonary aspergillosis and correlated with airway neutrophilia and airway obstruction. The interleukin-8-mediated neutrophil influx in allergic bronchopulmonary aspergillosis may induce lung damage via release of matrix metalloproteinase-9, potentially leading to bronchiectasis.