PT  - JOURNAL ARTICLE
AU  - Chin, Jia En
AU  - Hatfield, Cheryl A.
AU  - Winterrowd, Greg E.
AU  - Krzesicki, Raymond F.
AU  - Shull, Kathy L.
AU  - Fidler, Stephen F.
AU  - Kolbasa, Karen P.
AU  - Brashler, John R.
AU  - Griffin, Robert L.
AU  - Fleming, William E.
AU  - Justen, James M.
AU  - Banitt, Lee S.
AU  - Bundy, Gordon L.
AU  - Richards, Ivan M.
TI  - Preclinical Evaluation of Anti-inflammatory Activities of the Novel Pyrrolopyrimidine PNU-142731A, a Potential Treatment for Asthma
DP  - 1999 Jul 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 188--195
VI  - 290
IP  - 1
4099  - http://jpet.aspetjournals.org/content/290/1/188.short
4100  - http://jpet.aspetjournals.org/content/290/1/188.full
SO  - J Pharmacol Exp Ther1999 Jul 01; 290
AB  - The anti-inflammatory properties of a novel pyrrolopyrimidine, PNU-142731A, in a murine model of antigen-induced eosinophilic lung inflammation are described. PNU-142731A, when given orally, demonstrated a dose-related inhibition of eosinophil- and lymphocyte-rich accumulation in the airways of ovalbumin (OA)-sensitized and challenged (OA/OA) C57BL/6 mice. The magnitude of the suppression of lung inflammation was also dependent on length of treatment. Reductions in the levels of interleukin (IL)-5, IL-6, and IgA in the bronchoalveolar lavage fluid of treated OA/OA mice, when compared with vehicle-sensitized control mice (V/OA), were observed. Plasma concentrations of IL-5, total IgE, and OA-specific IgG1 were also lowered in OA/OA mice by treatment. Histological assessment of formalin-fixed lung tissue sections confirmed that the compound blocked the accumulation of eosinophils in the airway tissue. Furthermore, significantly less mucus glycoproteins were seen in the lungs of PNU-142731A-treated OA/OA mice. Reverse transcription-polymerase chain reaction of lung tissue from PNU-142731A-dosed OA/OA mice demonstrated that mRNA for Th2 cytokines was less than that in vehicle-treated OA/OA controls. OA-elicited production of IL-4 by disaggregated lung tissue cells from PNU-142371A-treated OA/OA mice was also less than that of controls. In contrast, the release of Th1 cytokines (IL-2 and interferon-γ) were elevated. Similarly, the OA-stimulated release of Th2 cytokines (IL-5 and IL-10) by splenocytes from PNU-142731A-treated OA/OA mice were inhibited. Combined therapy of OA/OA mice with PNU-142731A and suboptimal doses of dexamethasone revealed that PNU-142731A had steroid-sparing effects. These characteristics of PNU-142731A in a murine model of allergic tissue inflammation support its clinical development as a potential treatment for asthma. The American Society for Pharmacology and Experimental Therapeutics