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The effect of prostaglandins on the immunologic release of histoamine from human lung tissue
IO6
American Academy of Allergy
J. ALLERGYCLIN. IMMUNOL. FEBRUARY1973
beta adrenergic blocking agent propranolol~ enhanced the release of mediators. While adrenergic agents in other tissues appear to exert their modulating influences through changes in the levels of cyclic ~_MP, cholinergic stimulants appear to increase selectively the levels of cyclic guanosine 3'~5'-monophosphate (cyclic GMP). The cholinomimetic agent carbamylcholine (10-sM) was found to enhance the immunologic release of mediators from human nasal polyps. These findings closely parallel similar studies of the immunologic release of chemical mediators from human lung tissue, suggesting that the target cells responding to immunologic challenge in both the upper and lower respiratory tracts are closely related in regard to the eontrol mechanisms and products of the IgE-mediated reaction.
59. The effect of prostaglandins on the immunologic release of histamine from human lung tissue. A l f r e d I. T a u b e r , B.S., Michael K a l i n e r , M.D., D a n i e l J. Stechschulte, M.D., a n d K. F r a n k A u s t e n , M.D., Boston, Mass. Using human lung fragments passively sensitized with serum from atopic patients, the effects of the prostaglandins E 1 (PGE1) and F~ (PGP~) were studied on the antigeninduced release of histamine as assayed spectrofluorometrically and the concomitant changes in the tissue levels of cyclic AMP as determined by a protein binding assay. The prostaglandins were not inactivated during the period of incubation in human lung fragments in the absence of NAD § nor did they induce histamine release. PGE~ (5 • 10-~ to 5 x 10~M) produced a dose:response inhibition of histamine release in association with an increase in the tissue levels of cyclic AMP; these effects were appreciated within 15 seconds of the introduction of the agent, peaked within 60 seeonds~ and persisted through 60 minutes of incubation. The interaction of PGE~ with a specific receptor activating the enzyme adenylate cyelase was determined in 2 ways: combining the phosphodiesterase inhibitor aminophylline (10-4M) with PGE~ (5 • 10-sM) produced a synergistic inhibition of histamine release and elevation of cyclic AMP levels, and the beta adrenergie blocking agent propranolol had no effect on the PGE~ activity while preventing the effects of an equimolar concentration of the beta adrenergic stimulant isoproterenol. Comparing the ability of various agents to inhibit mediator release and raise cyclic AMP revealed that isoproterenol ~ norepinephrine PGE, ~ PGF2~ in order of potency. These data suggest that in human lung the prostagiandins are capable of inhibiting the immunologic release of histamine in association with an increase in cyclic AMP, but only at comparatively high concentrations.
60. Stimulation of adenylate cyclase by phentolamine in leukocytes of asthmatic children. P a t r i c i a J. Logsdon, B.A., D i a n e V. C a r n r i g h t , B.A., E l l i o t t Middleton, Jr., M.D., a n d R o n a l d G. Coffey, Ph.D., D e n v e r , Colo. Alpha adrenergic blocking agents enhance eateeholamine stimulation of adenylate cyclase in some tissues and have also been used in the treatment of asthma. Since adenylate cyclase of asthmatic leukoeytes responds poorly to isoproterenol (Iso), we added phentolamine (Phen) to leukocyte suspensions in vitro to attempt restoration of Iso responsiveness. Adenylate cyclase activity was assayed by the intact cell method following incorporation of 3H-adenine. Phen alone stimulated adenylate cyelase in normal leukocytes. Stimulation was diminished in cells from asthmatics, similar to the reduced Iso response. Stimulation was blocked by propranolol, and Phen had no effect on cyclic AMP phosphodiesterase. Combination of Phen and Iso produced an additive effect to stimulate adenylate cyclase in normal leukocytes; a synergistic effect was obtained in cells from asthmatics. Maximum stimulation in asthmatic leukocytes was similar to normal cells (line 5 of Table I). We conclude that Phen has a direct action on beta adrenergic receptors~ and may also block hypersensitive alpha receptors in asthmatic leukocytes, thereby permitting normal beta receptor responsiveness. These findings suggest a biochemical basis for the effectiveness of alpha adrenergic blockers in asthma.
American Academy of Allergy
J. ALLERGYCLIN. IMMUNOL. FEBRUARY1973
beta adrenergic blocking agent propranolol~ enhanced the release of mediators. While adrenergic agents in other tissues appear to exert their modulating influences through changes in the levels of cyclic ~_MP, cholinergic stimulants appear to increase selectively the levels of cyclic guanosine 3'~5'-monophosphate (cyclic GMP). The cholinomimetic agent carbamylcholine (10-sM) was found to enhance the immunologic release of mediators from human nasal polyps. These findings closely parallel similar studies of the immunologic release of chemical mediators from human lung tissue, suggesting that the target cells responding to immunologic challenge in both the upper and lower respiratory tracts are closely related in regard to the eontrol mechanisms and products of the IgE-mediated reaction.
59. The effect of prostaglandins on the immunologic release of histamine from human lung tissue. A l f r e d I. T a u b e r , B.S., Michael K a l i n e r , M.D., D a n i e l J. Stechschulte, M.D., a n d K. F r a n k A u s t e n , M.D., Boston, Mass. Using human lung fragments passively sensitized with serum from atopic patients, the effects of the prostaglandins E 1 (PGE1) and F~ (PGP~) were studied on the antigeninduced release of histamine as assayed spectrofluorometrically and the concomitant changes in the tissue levels of cyclic AMP as determined by a protein binding assay. The prostaglandins were not inactivated during the period of incubation in human lung fragments in the absence of NAD § nor did they induce histamine release. PGE~ (5 • 10-~ to 5 x 10~M) produced a dose:response inhibition of histamine release in association with an increase in the tissue levels of cyclic AMP; these effects were appreciated within 15 seconds of the introduction of the agent, peaked within 60 seeonds~ and persisted through 60 minutes of incubation. The interaction of PGE~ with a specific receptor activating the enzyme adenylate cyelase was determined in 2 ways: combining the phosphodiesterase inhibitor aminophylline (10-4M) with PGE~ (5 • 10-sM) produced a synergistic inhibition of histamine release and elevation of cyclic AMP levels, and the beta adrenergie blocking agent propranolol had no effect on the PGE~ activity while preventing the effects of an equimolar concentration of the beta adrenergic stimulant isoproterenol. Comparing the ability of various agents to inhibit mediator release and raise cyclic AMP revealed that isoproterenol ~ norepinephrine PGE, ~ PGF2~ in order of potency. These data suggest that in human lung the prostagiandins are capable of inhibiting the immunologic release of histamine in association with an increase in cyclic AMP, but only at comparatively high concentrations.
60. Stimulation of adenylate cyclase by phentolamine in leukocytes of asthmatic children. P a t r i c i a J. Logsdon, B.A., D i a n e V. C a r n r i g h t , B.A., E l l i o t t Middleton, Jr., M.D., a n d R o n a l d G. Coffey, Ph.D., D e n v e r , Colo. Alpha adrenergic blocking agents enhance eateeholamine stimulation of adenylate cyclase in some tissues and have also been used in the treatment of asthma. Since adenylate cyclase of asthmatic leukoeytes responds poorly to isoproterenol (Iso), we added phentolamine (Phen) to leukocyte suspensions in vitro to attempt restoration of Iso responsiveness. Adenylate cyclase activity was assayed by the intact cell method following incorporation of 3H-adenine. Phen alone stimulated adenylate cyelase in normal leukocytes. Stimulation was diminished in cells from asthmatics, similar to the reduced Iso response. Stimulation was blocked by propranolol, and Phen had no effect on cyclic AMP phosphodiesterase. Combination of Phen and Iso produced an additive effect to stimulate adenylate cyclase in normal leukocytes; a synergistic effect was obtained in cells from asthmatics. Maximum stimulation in asthmatic leukocytes was similar to normal cells (line 5 of Table I). We conclude that Phen has a direct action on beta adrenergic receptors~ and may also block hypersensitive alpha receptors in asthmatic leukocytes, thereby permitting normal beta receptor responsiveness. These findings suggest a biochemical basis for the effectiveness of alpha adrenergic blockers in asthma.