Apolipoprotein Mimetic Peptides: A New Approach for the Treatment of Asthma

Abstract

New treatments are needed for severe asthmatics to improve disease control and avoid severe toxicities associated with oral corticosteroids. We have used a murine model of house dust mite (HDM)-induced asthma to identify steroid-unresponsive genes that might represent targets for new therapeutic approaches for severe asthma. This strategy identified apolipoprotein E as a steroid-unresponsive gene with increased mRNA expression in the lungs of HDM-challenged mice. Furthermore, apolipoprotein E functioned as an endogenous negative regulator of airway hyperreactivity and goblet cell hyperplasia in experimental HDM-induced asthma. The ability of apolipoprotein E, which is expressed by lung macrophages, to attenuate AHR, and goblet cell hyperplasia is mediated by low density lipoprotein (LDL) receptors expressed by airway epithelial cells. Consistent with this, administration of an apolipoprotein E mimetic peptide, corresponding to amino acids 130–149 of the LDL receptor-binding domain of the holo-apoE protein, significantly reduced AHR and goblet cell hyperplasia in HDM-challenged apoE−/− mice. These findings identified the apolipoprotein E – LDL receptor pathway as a new druggable target for asthma that can be activated by administration of apoE-mimetic peptides. Similarly, apolipoprotein A-I may have therapeutic potential in asthma based upon its anti-inflammatory, anti-oxidative, and anti-fibrotic properties. Furthermore, administration of apolipoprotein A-I mimetic peptides has attenuated airway inflammation, airway remodeling, and airway hyperreactivity in murine models of experimental asthma. Thus, site-directed delivery of inhaled apolipoprotein E or apolipoprotein A-I mimetic peptides may represent novel treatment approaches that can be developed for asthma, including severe disease.

Novel candidate genes important for asthma and hypertension comorbidity revealed from associative gene networks

“…There are data suggesting that in cases of hypertension, the level of apoA-1 is diminished [79,80]. With this, in asthma patients, the level of apoA-1 in bronchoalveolar lavage fluid was significantly lower than in healthy controls [81,82]. ApoA-1 has a specific role in lipid metabolism, and is the major component of HDL particles in blood [83].…”

APOE ε4: The most prevalent yet understudied risk factor for Alzheimer's disease

“…2E and [42][43][44][45]). An alternative compensatory approach is to pharmacologically elevate the overall levels of brain apoE [46].…”

Revisiting “Good” and “Bad” Cholesterol. The Battle over Flow through Arteries Now Shifts to Flow through Airways

“…HDL is also the major source of the antioxidant vitamin E for the lung (13) and a major vehicle for a 1 -antitrypsin delivery to the lung (9). Moreover, HDL mimetics attenuate experimental asthma in mice (14), whereas diet-induced hypercholesterolemia enhances disease (15). Asthma is interestingly associated with reduced airspace apoA-I (16), increased plasma oxidized LDL (17), and deficient antiinflammatory function of HDL (18), suggesting lung disease may itself dysregulate local and systemic lipid metabolism, potentially in ways that may feed forward to promote disease.…”