Mechanism of Action
VPAC1 and VPAC2 Receptor Signaling
VIP binds VPAC1 (expressed in lung, liver, immune cells, brain) and VPAC2 (expressed in smooth muscle, brain, pancreas) receptors. Both couple to Gs proteins, stimulating adenylyl cyclase and raising cAMP. PKA activation mediates smooth muscle relaxation (vasodilation, bronchodilation), inhibition of mast cell degranulation, and suppression of pro-inflammatory cytokine production from macrophages, T cells, and dendritic cells.
Anti-Inflammatory and Immunomodulatory Effects
VIP is one of the most potent endogenous anti-inflammatory peptides. It inhibits TNF-alpha, IL-6, IL-12, and NO production from activated macrophages; suppresses Th1 and promotes Th2/Treg differentiation; reduces neutrophil trafficking; and prevents autoimmune tissue damage in multiple models. VIP-producing neurons in lymphoid organs directly regulate immune cell function, forming a neuroimmune axis.
Research Summary
Pulmonary Arterial Hypertension
Phase 2Inhaled VIP (Aviptadil) Phase 2 trial in PAH showed significant reductions in pulmonary vascular resistance and improvements in 6-minute walk distance. Phase 3 INCREASE-2 trial ongoing. Aviptadil demonstrated safety in multiple Phase 1/2 studies with promising hemodynamic effects at inhaled doses of 50-100 mcg 4x daily.
COVID-19 ARDS
Phase 2/3IV aviptadil (RLF-100) showed promising results in reducing mortality in mechanically ventilated COVID-19 ARDS patients in Phase 2 Israeli trial. US ACTIV-3 platform trial did not show benefit for IV VIP in hospitalized COVID-19; inhaled form results pending. VIP suppresses cytokine storm while protecting type II pneumocytes expressing high VPAC2.
Autoimmune and Neurological
PreclinicalCompelling preclinical evidence in rheumatoid arthritis, Crohn disease, multiple sclerosis, and Parkinson disease models. VIP treatment reduces joint inflammation, intestinal inflammation scores, EAE severity, and dopaminergic neuron loss. Translation to clinical trials ongoing for RA and IBD.
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Research Protocols
| Goal | Dose | Frequency | Route |
|---|---|---|---|
| Hemodynamic research (PAH) | 4-100 pmol/kg/min IV infusion or 50-100 mcg inhaled 4x daily | Continuous IV or 4x daily inhaled | Intravenous or inhalation |
| Anti-inflammatory research | 1-10 nmol/kg IV bolus (animal models); human doses under investigation | Varies | Intravenous |
Very short plasma half-life requires continuous infusion or inhaled route for systemic effects. Stable analogs (Ro 25-1553, PACAP) with longer half-lives are being developed for clinical use.
Interactions
Safety Profile
IV VIP causes transient facial flushing, hypotension, and headache due to systemic vasodilation, limiting IV use to controlled settings. Inhaled VIP is much better tolerated: mild cough and throat irritation; no significant systemic hypotension at approved inhaled doses. INCREASE-1 Phase 2 trial: no serious adverse events attributed to inhaled VIP. Gastrointestinal effects (increased motility) possible at high doses. No hepatic, renal, or hematological toxicity identified. The very short natural half-life provides a built-in safety margin for IV use.
References
- [1]Said SI, Mutt V. Polypeptide with broad biological activity: isolation from small intestine. Science. 1970;169(3951):1217-1218.
- [2]Leuchte HH, et al. Inhaled iloprost and vasoactive intestinal peptide for pulmonary vascular disease. Eur J Clin Invest. 2008;38(Suppl 2):23-27.
- [3]Gonzalez-Rey E, et al. Therapeutic effect of vasoactive intestinal peptide on experimental autoimmune encephalomyelitis. Am J Pathol. 2006;168(4):1179-1188.