Experiments performed by several laboratories have independently shown that administration of apoA-I or apoA-I mimetic peptides can attenuate the manifestations of allergen-induced experimental asthma. First, intranasal administration of the 5A apoA-I mimetic peptide to OVA-challenged Apoa-I knockout mice suppressed increases in neutrophilic airway inflammation. Similarly, administration of the apoA-I mimetic peptide, L-4F, to wild-type mice that received inhaled LPS reduced the number of BALF neutrophils. Second, systemic administration of the 5A apoA-I mimetic peptide coincident with intranasal administration of house dust mite to wild-type A/J mice significantly reduced the induction of airway inflammation with decreased numbers of BALF eosinophils, lymphocytes, and neutrophils. This reduction in airway inflammation was associated with decreases in type 2 cytokines (IL-4, IL-5, and IL-13), IL-17A, CC chemokines (CCL7, CCL11, CCL17, and CCL24), alternative macrophage activation, AHR, and mucous cell metaplasia. Third, intranasal administration of the D4F apoA-I mimetic peptide in a murine model of OVA-induced experimental asthma reduced airway inflammation, AHR, transforming growth factor-β, and lung collagen deposition, as well as total IgE and pro-inflammatory HDL in plasma. Lastly, intranasal administration of full-length human apoA-I to house dust mite-challenged mice reduced airway inflammation, with decreases in BALF eosinophils, neutrophils, lymphocytes, and macrophages, as well as AHR and lung levels of the airway epithelial cell-derived cytokines, IL-25, IL-33, and thymic stromal lymphopoietin, which promote allergic inflammation. Administration of apoA-I also increased the expression of airway epithelial cell tight junction proteins, as well as levels of lipoxin A4, an antiinflammatory and pro-resolving lipid mediator. Collectively, these experiments support the concept of developing apoA-I-based treatment approaches for asthma (Fig 1).