The objective of this proposal is to assess whether a specific autoantibody to the neuropeptide, Vasoactive Intestinal Peptide (VIP), is a contributory factor in hyperreactivity of the airways in asthma. The rationale for the proposal is: (1) airway hyperreactivity may arise from disturbed autonomic control of smooth muscle tone, (2) VIP is a likely mediator of physiologic nonadrenergic relaxation of respiratory smooth muscle, (3) specific autoantibody to VIP is present in some human plasmas, and, (4) asthmatic plasmas show increased specific binding to VIP, compared to normal plasmas. Specifically, it will be experimentally determined (1) whether the affinity and/or concentration of the VIP-binding factor in asthmatics is greater than in healthy subjects, (2) whether the VIP-binding factor in asthmatic plasma is an autoantibody, and (3) whether the VIP-binding factor interferes with (i) the binding of VIP to its receptors on lung membranes, (ii) the stimulation of adenylate cyclase activity in lung membranes by VIP, and, (iii) relaxation of tracheal strips in vitro by VIP. The methods to be employed to reach these objectives are: (1) radioassay of the specific-VIP binding by plasma, and computation of the affinity and binding capacity by the method of Scatchard (2) immune-precipitation of the VIP-binding activity with specific antisera against human immunoglobulins, and its chromatographic characterization, in order to confirm that it is an antibody, (3) assay of the potency of VIP treated with VIP-antibody to: (i) bind to lung membrane receptors in a radioreceptor assay, (ii) stimulate adenylate cyclase activity as measured by radioimmunoassay of cyclic AMP generated by in vitro incubation of guinea pig lung membranes, and (iii) relax perfused tracheal strips from guinea pig. If the VIP-binding factor in asthmatic plasma is an antibody, if it effectively competes with tissue receptors for VIP, and if it neutralizes the bioactivity of VIP in vitro, it will be concluded that autoantibody to VIP may contribute to the airway hyperreactivity of asthma.
| Paul, S; Volle, D J; Beach, C M et al. (1989) Catalytic hydrolysis of vasoactive intestinal peptide by human autoantibody. Science 244:1158-62 |
| Paul, S (1989) Decreased selectivity of vasoactive intestinal peptide receptors by GTP. Biochem Pharmacol 38:699-702 |
| Paul, S; Chou, J; Said, S I (1988) Regulatory aspects of the vasoactive intestinal peptide receptor in lung. Ann N Y Acad Sci 527:282-95 |
| Paul, S; Said, S I (1988) Human autoantibody to vasoactive intestinal peptide: increased incidence in muscular exercise. Life Sci 43:1079-84 |
| Paul, S; Chou, J; Kubota, E (1987) High affinity peptide histidine isoleucine-preferring receptors in rat liver. Life Sci 41:2373-80 |
