Effects of dipeptidyl peptidase-4 inhibition in an animal model of experimental asthma: a matter of dose, route, and time

Abstract

The CD26-associated enzymatic activity of dipeptidyl peptidase-4 (DPP4) as well as the recruitment of CD26+ T cells increase under allergic airway inflammation. Furthermore, genetic deficiency of CD26/DPP4 exerts protective effects in experimental asthma. Therefore, CD26/DPP4 might represent a novel therapeutic target in asthma. To study the effects of pharmacological inhibition of DPP4 on allergic airway inflammation the DPP4-inhibitor isoleucine thiazolidide was tested using different doses at different time points (at sensitization, immediately before and simultaneously with the allergen challenge, as well as continuously via drinking water), and different routes (intraperitoneal, oral, and by inhalation). Allergic-like airway inflammation was induced in Fischer 344 rats (Charles River) sensitized against ovalbumin (OVA) using OVA aerosols. Intraperitoneal application of the DPP4 inhibitor showed effects neither at sensitization nor at challenge, whereas a continuous application via drinking water using high doses of the inhibitor led to an aggravation of the histomorphological signs of airway inflammation. In contrast, aerosolization of the DPP4 inhibitor simultaneously with the allergen significantly reduced airway hyperresponsiveness and ameliorated histopathological signs compared to controls. In addition, this treatment resulted in increased mRNA levels of surfactant proteins, suggesting an involvement of DPP4 inhibitors in surfactant metabolism in OVA-challenged rats. Continuous systemic inhibition of DPP4 via the oral route aggravates allergic airway inflammation. In contrast, topical inhibition of DPP4 exerts potential protective effects, and further research in humans is needed.

DPP4 Inhibitors increase differentially the expression of surfactant proteins in Fischer 344 rats

“…Our results confirm our hypothesis that the application of DPP4 inhibitors leads not only to an increased synthesis of SP in allergic‐like airway inflammation (Stephan et al . ) but also partially in healthy control lungs (Table ) however at former time points (Figs ) than in asthma‐induced rats (Stephan et al . ).…”

“…Surprisingly, pharmacological inhibition of DPP4 in asthmatic rats resulted in an significant increase of all SPs at the mRNA level (Stephan et al . ). Therefore, the question came up if these inhibitors would influence also the surfactant protein expression in healthy DPP4/CD26 + rats in comparison with positive controls such as glucosteroides or negative controls such as inactive inhibitors.…”

The emerging role of dipeptidyl-peptidase-4 as a therapeutic target in lung disease

“…Indeed, Stephan et al have shown that continuous systemic inhibition of DPP-4 mediated by oral administration exacerbates airway inflammation in an experimental model of asthma. Conversely, topical inhibition was effective and given its potential impact on this prevalent and significant respiratory disease, further research in humans is merited [58].…”

Biomarkers in Severe Asthma

“…DPP4 inhibition has effects on airway inflammation in animal models that depend on the route of administration (oral, aerosolized, topical). 39 Studies of DPP4 in human airway inflammation are limited. Other potential biomarkers of type 2 inflammation include urinary bromotyrosine (BrTyr), 40,41 monocyte chemoattractant protein-4 (MCP4), and eotaxin-2.…”