ß2 adrenergic agonist suppresses eosinophil-induced epithelial-to-mesenchymal transition of bronchial epithelial cells.

BACKGROUND: Epithelial-mesenchymal transition is currently recognized as an important mechanism for the increased number of myofibroblasts in cancer and fibrotic diseases. We have already reported that epithelial-mesenchymal transition is involved in airway remodeling induced by eosinophils. Procaterol is a selective and full ß2 adrenergic agonist that is used as a rescue of asthmatic attack inhaler form and orally as a controller. In this study, we evaluated whether procaterol can suppress epithelial-mesenchymal transition of airway epithelial cells induced by eosinophils. METHODS: Epithelial-mesenchymal transition was assessed using a co-culture system of human bronchial epithelial cells and primary human eosinophils or an eosinophilic leukemia cell line. RESULTS: Procaterol significantly inhibited co-culture associated morphological changes of bronchial epithelial cells, decreased the expression of vimentin, and increased the expression of E-cadherin compared to control. Butoxamine, a specific ß2-adrenergic antagonist, significantly blocked changes induced by procaterol. In addition, procaterol inhibited the expression of adhesion molecules induced during the interaction between eosinophils and bronchial epithelial cells, suggesting the involvement of adhesion molecules in the process of epithelial-mesenchymal transition. Forskolin, a cyclic adenosine monophosphate-promoting agent, exhibits similar inhibitory activity of procaterol. CONCLUSIONS: Overall, these observations support the beneficial effect of procaterol on airway remodeling frequently associated with chronic obstructive pulmonary diseases.

Bronchodilator Inhalation During Ex Vivo Lung Perfusion Improves Posttransplant Graft Function After Warm Ischemia.

BACKGROUND: We hypothesized that an injured lung graft from donation after cardiac death donors could be reconditioned before transplantation using an ex vivo lung perfusion (EVLP) system and ventilation with high-dose short-acting ß2-adrenergic receptor agonists. METHODS: Cardiac arrest was induced in a canine model by intravenous potassium chloride injection. Lungs were randomly assigned to two groups after 150 minutes of warm ischemia: inhalation of 1,400 µg of procaterol (BETA group, n = 5) or control group receiving solvent (CON group, n = 5) during EVLP. Left lungs were transplanted after 120 minutes of EVLP. Functional variables, tissue adenosine 5'-triphosphate levels, and tissue cyclic adenosine monophosphate levels were measured 240 minutes after transplantation. RESULTS: Physiologic pulmonary function was similar at the end of EVLP in both groups. However, significantly better graft oxygenation, dynamic pulmonary compliance, and reduced pulmonary vascular resistance were observed in the BETA group than in the CON group 240 minutes after transplantation. No severe adverse effects were observed after lung transplantation in the BETA group. Lung tissue adenosine 5'-triphosphate levels and cyclic adenosine monophosphate levels were significantly higher in the BETA group than in the CON group at the end of EVLP and at 240 minutes after transplantation. CONCLUSIONS: High-dose nebulized procaterol during EVLP ameliorated lung graft dysfunction at the early posttransplantation period without severe adverse effects. These data suggest that lung reconditioning with procaterol ventilation during EVLP improves lung graft function after transplantation.

ß2-Adrenoreceptor Agonist Inhalation During Ex Vivo Lung Perfusion Attenuates Lung Injury.

BACKGROUND: Attenuation of ischemia reperfusion injury (IRI) is important in lung transplantation. Our group previously reported that ß2-adrenoreceptor agonist inhalation during the period before procurement successfully attenuated IRI in donated lungs after cardiac death. We therefore hypothesized that ß2-adrenoreceptor agonist inhalation during ex vivo lung perfusion (EVLP) after procurement might also have a protective effect. METHODS: Cardiac-dead beagles were left at room temperature for 210 minutes, and all lungs were subsequently procured and subjected to EVLP for 240 minutes. The beagles were allocated to 2 groups: the ß2 group (receiving an aerosolized ß2-adrenoreceptor agonist 20 minutes after initiation of EVLP; n = 7) and the control group (receiving an aerosolized control solvent at the same time point; n = 6). Physiologic data, including lung function, were evaluated during EVLP. RESULTS: The ß2 group showed significantly lower peak airway pressure and pulmonary artery pressure than the control group. Dynamic pulmonary compliance was higher, pulmonary vascular resistance (PVR) was lower, and the wet-to-dry lung weight ratio was lower in the ß2 group than in the control group. Cyclic adenosine monophosphate (cAMP) and total adenosine nucleotide (TAN) levels in lung tissue after EVLP were higher in the ß2 group than in the control group. The ß2 group also showed more cystic fibrosis transmembrane conductance regulator (CFTR) gene expression. CONCLUSIONS: After procurement, ß2-adrenoreceptor agonist inhalation during EVLP attenuates lung injury in a canine model of organ donation after cardiac death.

The effect of ß-2 adrenoreceptor agonist inhalation on lungs donated after cardiac death in a canine lung transplantation model.

BACKGROUND: It is a matter of great importance in a donation after cardiac death to attenuate ischemia-reperfusion injury (IRI) related to the inevitable warm ischemic time. METHODS: Donor dogs were rendered cardiac-dead and left at room temperature. The dogs were allocated into 2 groups: the ß-2 group (n = 5) received an aerosolized ß-2 adrenoreceptor agonist (procaterol, 350 µg) and ventilation with 100% oxygen for 60 minutes starting at 240 minutes after cardiac arrest, and the control group (n = 6) received an aerosolized control solvent with the ventilation. Lungs were recovered 300 minutes after cardiac arrest. Recipient dogs underwent left single-lung transplantation to evaluate the functions of the left transplanted lung for 240 minutes after the reperfusion. RESULTS: Oxygenation and dynamic compliance were significantly higher in the ß-2 group than in the control group. The ß-2 group revealed significantly higher levels of cyclic adenosine monophosphate and high-energy phosphates in the donor lung after the inhalation than before it. Histologic findings revealed that the ß-2 group had less edema and fewer inflammatory cells. CONCLUSION: Our results suggest that ß-2 adrenoreceptor agonist inhalation during the pre-procurement period may ameliorate IRI.

Adrenal influences on the inhibitory effects of procaterol, a selective Beta-two-adrenoceptor agonist, on antigen-induced airway microvascular leakage and bronchoconstriction in Guinea pigs.

While the guinea pig has been the preferred choice for use as a model of allergic bronchial asthma in the evaluation of anti-asthmatic drugs, it has been shown that antigen-induced bronchoconstriction in guinea pigs is attenuated by epinephrine released from the adrenal gland. In order to investigate the possible influence of the adrenal gland on the effects of antiexudative and bronchodilative drugs on antigen-induced airway responses, we examined the inhibitory effects of procaterol, a selective beta(2)-adrenoceptor agonist, on antigen-induced airway microvascular leakage and bronchoconstriction in adrenalectomized guinea pigs and compared them with the drug's effects in sham-operated animals. Guinea pigs sensitized passively with anti-ovalbumin (OA) guinea-pig serum were adrenalectomized or sham-operated under urethane anesthesia and examined 30 min after surgery in the following experiments. (1) Animals were intravenously administered Evans blue dye to quantify airway plasma exudation, and then OA was inhaled for 10 min while measuring pulmonary inflation pressure, a parameter of bronchoconstriction. Procaterol (1, 3, 10, or 30 microg/kg) or saline (control) was administered into the airways 10 min prior to OA inhalation. The amount of extravasated Evans blue dye in the airways was calculated. (2) Venous blood samples were collected during OA or saline inhalation and plasma catecholamine levels were compared. In control animals, OA-induced increases in both the amount of Evans blue dye and in pulmonary inflation pressure were markedly greater in adrenalectomized animals than in sham-operated animals. Procaterol dose-dependently inhibited OA-induced airway microvascular leakage and bronchoconstriction, and its effects were more potent in adrenalectomized animals (significant at 1 microg/kg and higher) than in sham-operated animals (significant at 10 microg/kg and higher). Although the plasma concentration of epinephrine during OA inhalation was approximately 3 times higher than that during saline inhalation in sham-operated animals, no difference was seen in adrenalectomized animals. In conclusion, while procaterol essentially possesses pronounced inhibitory effects on antigen-induced airway microvascular leakage and bronchoconstriction in guinea pigs, the effects are considerably masked by epinephrine released from the adrenal gland.

Beta2-adrenergic receptor genotype-related changes in cAMP levels in peripheral blood mononuclear cells after multiple-dose oral procaterol.

PURPOSE: To evaluate the beta2-adrenergic receptor (beta2AR) genotype frequency in the Japanese population and the relationship between beta2AR genotype at amino acid position 16 (beta2AR-16) and desensitization to beta2-agonist ex vivo. METHODS: The beta2AR genotypes at amino acid positions 16, 27, and 164 of 92 healthy Japanese subjects were determined by polymerase chain reaction-restriction fragment-length polymorphism. The relationship between the beta2AR-16 genotype and the desensitization to beta2-agonist was examined in 10 male subjects ex vivo. Procaterol tablet (HCl salt, 50 microg, Meptin) was given orally for 5 days, and peripheral blood was obtained before and after 5 days of consecutive medications followed by the assessment of the intracellular cAMP levels in peripheral blood mononuclear cells after incubation with or without procaterol hydrochloride (0-1000 ng/mL). RESULTS: Allele frequency was Arg16:Gly16 = 46%:54%, Gln27: Glu27 = 92%:8%, and Thr164:Ile164 = 100%:0%, respectively. The cAMP levels were increased by incubation with procaterol hydrochloride, and the increase was suppressed after 5 days of consecutive medications. The suppression was more significant in the homozygote for Gly16 than the homozygote for Arg16. CONCLUSIONS: The desensitization to beta2-agonist was associated more frequently with the mutation at beta2AR-16 (Gly16).

Inhibitory effects of theophylline and procaterol on eosinophil function.

Eosinophils play a crucial role in bronchial asthma. As theophylline and procaterol (beta 2-agonist) are used for the treatment of bronchial asthma, the specific functions of eosinophils in the presence of granulocyte/macrophage colony-stimulating factor (GM-CSF) or platelet activating factor (PAF) were examined using theophylline and procaterol alone and in combination. Eosinophil degranulation induced by PAF or GM-CSF was inhibited by theophylline (10(-6) M-10(-3) M and 10(-6) M to 10(-3) M, respectively) and procaterol (10(-7) M-10(-5) M and 10(-7) M-10(-5) M, respectively). The combination of 10(-4) M theophylline and various concentrations of procaterol provided higher inhibition than 10(-4) M theophylline or procaterol (10(-7) M-10(-5) M). CD11b, which is a triggering molecule for human eosinophil degranulation, showed a significantly inhibited expression of PAF stimulation with 10(-4) M theophylline. CD11b and another triggering molecule for eosinophil degranulation, CD18, showed a significantly inhibited expression of PAF stimulation using a combination of 10(-4) M theophylline and various concentrations of procaterol (10(-5) M-10(-7) M) compared with the inhibition of 10(-4) M theophylline or procaterol (10(-5) M-10(-7) M), but GM-CSF-stimulated eosinophils were not inhibited. Taken collectively, theophylline and/or procaterol have anti-inflammatory effects.

Maximum bronchodilator effect of pirbuterol and procaterol administered as sprays with and without an aerochamber

Objective of the study: To determine the maximal bronchodilator dose of procaterol and pirbuterol administered by inhalation with an without an aerochamber (Aerocâmera) to children with acute brinchial asthma attacks. Type of study: Prospective. 18 children (6-15 years of age) with acute bronchial asthma attacks (FEV1 < 80 per cents of the predicted value) received pirbuterol (N = 10) or procaterol (N = 8) by metered-dose inhaler, one puff every 5 minutes, for a total of five doses. During another acute attack, the same patient received the same medication with the aid of a spacer (Aerocâmera). Clinical evaluation and pulmonary function tests were performed 5 minutes after each inhaled dose. Results: For both drugs, maximal bronchodilation was obtained after the second dose. No significant side effects were observed even after procaterol doses of 50 µg or pirbuterol doses of 1000 µg. The results were unaffected by the use of the spacer. Conclusions: The doses that induced maximal bronchodilation were 400 µg pirbuterol and 20 µg procaterol Although the spacer did not change the results, it is a valuable aid for patients who have difficulty in using the metered-dose inhaler (M.D.I.)