Desensitization of beta-adrenergic receptors in lung injury induced by 2-chloroethyl ethyl sulfide, a mustard analog.
2-Choloroethyl Ethyl Sulfide (CEES) exposure causes inflammatory lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary fibrosis. This may be associated with oxidative stress, which has been implicated in the desensitization of beta-adrenergic receptors (beta-ARs). The objective of this study was to investigate whether lung injury induced by intratracheal CEES exposure (2 mg/kg body weight) causes desensitization of beta-ARs. The animals were sacrificed after 7 days and lungs were removed. Lung injury was established by measuring the leakage of iodinated-bovine serum albumin ([(125)I]-BSA) into lung tissue. Receptor-binding characteristics were determined by measuring the binding of [(3)H] dihydroalprenolol ([(3)H] DHA) (0.5-24 nM) to membrane fraction in the presence and absence of DLDL-propranolol (10 micro M). Both high- and low-affinity beta-ARs were identified in the lung. Binding capacity was significantly higher in low-affinity site in both control and experimental groups. Although CEES exposure did not change K(D) and B(max) at the high-affinity site, it significantly decreased both K(D) and B(max) at low affinity sites. A 20% decrease in beta(2)-AR mRNA level and a 60% decrease in membrane protein levels were observed in the experimental group. Furthermore, there was significantly less stimulation of adenylate cyclase activity by both cholera toxin and isoproterenol in the experimental group in comparison to the control group. Treatment of lungs with 3-isobutyl-1-methylxanthine (IBMX), an inhibitor of phosphodiesterase (PDE) could not abolish the difference between the control group and the experimental group on the stimulation of the adenylate cyclase activity. Thus, our study indicates that CEES-induced lung injury is associated with desensitization of beta(2)-AR.
Kabir
Syeda M
SM
Department of Cancer Biology, Meharry Medical College, 1005 David Todd Blvd., Nashville, TN 37208, USA.
Mukherjee
Shyamali
S
Rajaratnam
Veera
V
Smith
Milton G
MG
Das
Salil K
SK
D000818:Animals; D002772:Cholera Toxin / Q000633:toxicity; D000242:Cyclic AMP / Q000378:metabolism; D004082:Dihydroalprenolol / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006168:Guinea Pigs; D042541:Intracellular Space / Q000187:drug effects / Q000378:metabolism; D055370:Lung Injury / Q000139:chemically induced / Q000378:metabolism*; D008297:Male; D008566:Membranes / Q000187:drug effects / Q000378:metabolism; D009151:Mustard Gas / Q000031:analogs & derivatives* / Q000633:toxicity; D011943:Receptors, Adrenergic, beta / Q000235:genetics / Q000378:metabolism*
D011943:Receptors, Adrenergic, beta; D004082:Dihydroalprenolol; C031278:2-chloroethyl ethyl sulfide; D002772:Cholera Toxin; D000242:Cyclic AMP; D009151:Mustard Gas