Bronchodilator tolerance and rebound bronchoconstriction during regular inhaled β -agonist treatment

AbstractThere is uncertainty about the development of airway tolerance to β -agonists and the phenomenon of rebound bronchoconstriction on β -agonist withdrawal. We have recently completed a study of the regular terbutaline and budesonide treatment in asthma. We report our observations on the effect of starting and stopping terbutaline treatment on morning and evening peak flows.The study was a randomized four-way, double-dummy, cross-over comparison of regular inhaled terbutaline (500–1000 μ g four times daily), budesonide, combined treatment and matching placebo. Each treatment was given for 6 weeks following a 4 week single-blind placebo washout. Ipratropium was used for symptom relief. No other asthma medication was permitted during either the treatment or wash-out periods. Evaluable data were obtained from 52 subjects for both placebo and terbutaline treatment. Changes in mean morning and evening peak flows during terbutaline treatment were compared to the baseline peak flows during the last 2 weeks of the preceding washout. The peak flow changes on stopping terbutaline were also analysed.Mean morning peak flow was not significantly different during terbutaline treatment when compared to either baseline or placebo treatment. Evening peak flows were significantly higher during terbutaline treatment [mean increase 23·1l min−1(95%CI=18·8, 27·4)]. Analysis of the peak flow changes on a day-by-day basis revealed an initial increase in morning peak flows for the first 2 days of treatment of 19·2 and 13·4l min−1[increases of 25·0 and 17·3l min−1in comparison with the corresponding values during placebo (P<0·01)] followed by a return to baseline. The increase in evening peak flows was also greater for the first 2 days of treatment than for the remainder of the treatment period (P<0·01). On ceasing terbutaline treatment there was a fall in mean morning peak flow below the baseline on the following morning of 21·6l min−1(P<0·05 compared to placebo).The temporary increase in morning peak flows and greater than expected rise in evening peak flows for the first 2 days of treatment suggest the development of tolerance to the bronchodilator effect of terbutaline. Similarly, the fall in morning peak flows on treatment withdrawal suggests rebound bronchoconstriction. These effects are likely to be mediated by downregulation of the β -receptor during treatment. The clinical significance of these changes is uncertain in view of the stability of overall asthma control during terbutaline treatment, but sudden withdrawal of β -agonist treatment could conceivably lead to a deterioration in asthma control

Co-culture of mechanically injured cartilage with joint capsule tissue alters chondrocyte expression patterns and increases ADAMTS5 production

We studied changes in chondrocyte gene expression, aggrecan degradation, and aggrecanase production and activity in normal and mechanically injured cartilage co-cultured with joint capsule tissue. Chondrocyte expression of 21 genes was measured at 1, 2, 4, 6, 12, and 24 h after treatment; clustering analysis enabled identification of co-expression profiles. Aggrecan fragments retained in cartilage and released to medium and loss of cartilage sGAG were quantified. Increased expression of MMP-13 and ADAMTS4 clustered with effects of co-culture, while increased expression of ADAMTS5, MMP-3, TGF-β, c-fos, c-jun clustered with cartilage injury. ADAMTS5 protein within cartilage (immunohistochemistry) increased following injury and with co-culture. Cartilage sGAG decreased over 16-days, most severely following injury plus co-culture. Cartilage aggrecan was cleaved at aggrecanase sites in the interglobular and C-terminal domains, resulting in loss of the G3 domain, especially after injury plus co-culture. Together, these results support the hypothesis that interactions between injured cartilage and other joint tissues are important in matrix catabolism after joint injury

Proteoglycan 4 downregulation in a sheep meniscectomy model of early osteoarthritis

Osteoarthritis is a disease of multifactorial aetiology characterised by progressive breakdown of articular cartilage. In the early stages of the disease, changes become apparent in the superficial zone of articular cartilage, including fibrillation and fissuring. Normally, a monolayer of lubricating molecules is adsorbed on the surface of cartilage and contributes to the minimal friction and wear properties of synovial joints. Proteoglycan 4 is the lubricating glycoprotein believed to be primarily responsible for this boundary lubrication. Here we have used an established ovine meniscectomy model of osteoarthritis, in which typical degenerative changes are observed in the operated knee joints at three months after surgery, to evaluate alterations in proteoglycan 4 expression and localisation in the early phases of the disease. In normal control joints, proteoglycan 4 was immunolocalised in the superficial zone of cartilage, particularly in those regions of the knee joint covered by a meniscus. After the onset of early osteoarthritis, we demonstrated a loss of cellular proteoglycan 4 immunostaining in degenerative articular cartilage, accompanied by a significant (p < 0.01) decrease in corresponding mRNA levels. Early loss of proteoglycan 4 from the cartilage surface in association with a decrease in its expression by superficial-zone chondrocytes might have a role in the pathogenesis of osteoarthritis