Antigen-specific IgE and IgA antibodies in bronchoalveolar lavage fluid are associated with stronger antigen-induced late phase reactions.

The mechanism(s) leading to the development of late phase allergic reactions is (are) unknown. Previous studies have indicated that a relationship between serum IgE and the late phase exists. To explore the relationships between allergen-specific immunoglobulins in bronchoalveolar lavage (BAL) fluids and the magnitude of airflow limitation during the late phase response to inhaled allergen. Ragweed-specific IgE, IgA, secretory IgA (sIgA) and IgG were measured in BAL fluid and in the serum 1-5 weeks before whole lung antigen challenge with ragweed extract, in 16 ragweed allergic asthmatics. In addition, BAL and serum eosinophil cationic protein (ECP) and BAL fibrinogen levels were determined and BAL cells counted and differentiated. The latter procedures were repeated in a second BAL performed 24 h after the end of the ragweed challenge. After the challenge, lung function was monitored hourly for 8 h, to record the magnitude of airflow limitation. Ragweed-specific immunoglobulins were detected in 25% to 37.5% of BAL samples. Compared to the subjects with undetectable BAL fluid ragweed-specific IgE levels at baseline, those with detectable antibodies had stronger late phase reactions as determined by the nadir of FEV1 between hours 4 and 8 after the ragweed inhalation challenge (P = 0.0007). Allergen-induced changes in BAL ECP and fibrinogen levels were also higher in those subjects with detectable ragweed-specific IgE in baseline fluids (P = 0.03 and P = 0.005, respectively). Significant relationships between BAL antigen-specific IgA, serum ragweed-specific IgE and IgA and the late phase reaction were also found. The results of this study point towards the possibility that allergen-specific IgE and IgA may be independently involved in the pathogenesis of the late phase reaction. This notion merits further exploration.

Evidence that cyclosporine G is less deleterious to rat bone in vivo than cyclosporine A.

We have previously shown that CsA administration to rats causes a high turnover bone loss with bone resorption exceeding bone formation. Similar findings have been reported in renal and cardiac transplantation patients administered CsA. Cyclosporine-G (CsG), a natural equipotent immunosuppressive analogue of CsA, has been shown to be less nephrotoxic than CsA. We therefore compared the effects of CsG and CsA on bone mineral metabolism. Sixty male Sprague-Dawley rats were divided into 3 equal groups as follows: group A (n = 20) was the control; group B (n = 20) received CsA 15 mg/kg by daily gavage; and group C received CsG 15 mg/kg by daily gavage for 28 days. Rats were bled weekly for measurement of circulating biochemical parameters of bone mineral metabolism and after sacrifice on day 28, the tibiae were removed for histomorphometric analysis. The tibial bone histomorphometry revealed that the percentage of bone volume was significantly reduced, and the osteoclast count increased in both the CsA and CsG group, but significantly less so in the CsG than the CsA group. Parameters reflecting bone formation in the CsG group were similar to controls but significantly different from the CsA group. Bone Gla protein levels in the CsA group were significantly increased compared with the control and CsG groups from day 14. Serum 1,25 dihydroxyvitamin D was increased significantly in the CsA group on days 14 and 28 compared with both control and CsG groups, and was significantly elevated in the CsG group compared with controls on the same days. We conclude that CsG is significantly less deleterious to bone mineral metabolism than CsA in the rat in vivo.

1,25 Dihydroxyvitamin D3 modifies cyclosporine-induced bone loss.

We have previously shown that cyclosporin A (CsA) produces high bone remodeling with resorption exceeding formation and loss of bone volume in the rat. This may have important clinical implications where CsA is widely used in organ transplantation. 1,25 dihydroxyvitamin D3 (1,25(OH)2D3) is a bone mineralizing hormone which also has immune modifying properties. Consequently, we studied the effect of combined CsA and 1,25(OH)2D3 administration over 28 days in four groups of rats. Group A received vehicle (n = 10), group B CsA (15 mg/kg) (n = 10) alone, group C 1,25(OH)2D3 plus CsA (n = 15), and group D 1,25(OH)2D3 alone (20 ng/100 g) (n = 15). Rats were bled periodically at day 0, 7, 14, and 28 and Ca, parathyroid hormone (PTH), 1,25(OH)2D, osteocalcin (bone Gla-protein, BGP), BUN, and creatinine were measured. Rats were sacrificed on day 28 and bones were examined histomorphometrically. Compared to controls, CsA resulted in significant elevation of BGP and a transient increase in 1,25(OH)2D with excess bone remodeling and loss of bone volume. 1,25(OH)2D3 administration produced hypercalcemia, a significant rise in BGP, with suppression of PTH and increased osteoid volume. Combined therapy prevented the loss of bone volume probably due to increased osteoid tissue and enhanced osteoblast activity. Renal dysfunction, a side-affect of CsA, was not a factor. In conclusion, 1,25(OH)2D3 combined with CsA restores bone volume which is accompanied by increases in serum calcium and BGP.

Combined treatment with cyclosporin A and cortisone acetate minimizes the adverse bone effects of either agent alone.

Although cyclosporin A (CsA) and cortisone acetate (CRT) adversely affect bone, their combined effect on bone is unknown. Sprague Dawley rats were therefore administered either vehicle or CsA (7.5 mg/kg/day) by gavage and saline or CRT (2 mg/100 mg/day) by s.c. injection for 28 days. Group A received vehicle plus saline, group B CsA plus saline, group C vehicle plus CRT, and group D CsA/CRT. Serial bloods were sampled over a 28-day period for ionized calcium (Ca), PTH, 1,25 dihydroxyvitamin D (1,25(OH)2D), and bone gla protein (BGP osteocalcin) and tibia were examined on day 28 for histomorphometry. Results were compared with group A. Ca and PTH levels in groups B, C, and D were similar to those in group A during the study period. Group B had lower body weights, elevated levels of BGP, and an increase in 1,25(OH)2D. Group C developed weight loss and a decrease in BGP and 1,25(OH)2D. Group D had weight loss, BGP levels between those of group A and group C, and 1,25(OH)2D values similar to group A. Bone histomorphometry revealed high turnover osteopenia in group B and hyperostosis in group C with a decrease in bone formation and osteoclastlike cells. Combination therapy returned these to control values. In conclusion, the adverse effects of either CsA or CRT on bone in rats are minimized by combined therapy.

The effect of cyclosporin A administration and its withdrawal on bone mineral metabolism in the rat.

The in vivo administration of cyclosporin A (CsA) has been associated with significant bone loss and increased bone remodeling. To observe whether these changes are reversible, we have investigated the consequences of the administration and withdrawal of CsA immunotherapy on bone mineral metabolism. Three groups of Sprague-Dawley rats were studied for 28 days. Group A received vehicle, and group B received CsA (15 mg/kg BW) for 28 days, while group C received CsA (15 mg/kg BW) for 14 days and then vehicle from days 15-28 by daily gavage. Serum ionized calcium (Ca2+), PTH, bone gla protein, blood urea nitrogen, creatinine, magnesium, phosphorus, and 1.25-dihydroxyvitamin D were measured weekly. Bone histomorphometry was analyzed on days 14 and 28 in groups A and B and on day 28 in group C. CsA administration resulted in reversible hypomagnesemia and mild transient elevation in circulating 1,25-dihydroxyvitamin D levels with no change in Ca2+, PTH, blood urea nitrogen, or phosphorus. Serum bone gla protein levels were significantly increased (P less than 0.002) during CsA therapy, but tended to return to control values after CsA withdrawal. Enhanced bone remodeling and significant trabecular bone loss accompanied CsA administration. Withdrawal of CsA resulted in all of the histomorphometric parameters, except for bone volume, returning to control values within 2 weeks. Incomplete restoration of bone volume occurred 5 weeks after CsA withdrawal. This limited restoration of bone volume despite CsA withdrawal may have important clinical implications.

A technique for foreign body removal from the airway.

We report a case in whom a foreign body was retrieved from the peripheral airway using a fibreoptic bronchoscope and a modified suction tube.