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Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor.
Int Immunopharmacol 2012; 12(1):59-63II

Abstract

Neutrophil-dominant pulmonary inflammation is an important feature of chronic obstructive pulmonary disease (COPD). Here, we evaluated the in vitro and in vivo anti-neutrophilic inflammatory activities of ASP3258, a novel, orally active, and selective phosphodiesterase (PDE) 4 inhibitor with anti-inflammatory potency comparable to that of second-generation compound roflumilast but with lower emetic activity in vivo. In in vitro experiments using human peripheral blood neutrophils, PDE4 inhibitors ASP3258, cilomilast, and roflumilast inhibited fMLP-induced superoxide production in a concentration-dependent manner with IC50 values of 5.0, 96, and 4.7 nM, respectively. ASP3258, cilomilast, and roflumilast also attenuated fMLP-induced neutrophil chemotaxis in a concentration-dependent manner with IC30 values of 18, 270, and 9.7 nM, respectively. In contrast, the glucocorticoid prednisolone inhibited neither superoxide production nor chemotaxis up to 1 μM. In a rat model of lipopolysaccharide (LPS)-induced lung inflammation, orally administered ASP3258, cilomilast, roflumilast, and prednisolone (at 10 or 30 mg/kg) dose-dependently attenuated pulmonary accumulation of neutrophils. The inhibitory effect of ASP3258 was more potent than cilomilast and almost the same as roflumilast and prednisolone. Treatment with ASP3258 inhibited the elevation of TNF-α in the bronchoalveolar lavage fluid following LPS instillation. Histological examination revealed significant inhibition of neutrophil and macrophage infiltration into alveoli by ASP3258. Overall, these findings suggest that ASP3258 has therapeutic potential for treating neutrophilic inflammation such as COPD, partly through direct inhibition of neutrophil activation as well as possibly through inhibition of the TNF-α-mediated pathway.

Authors+Show Affiliations

Pharmacology Research Labs., Drug Discovery Research, Astellas Pharma Inc., 21 Miyukigaoka, Tsukuba-shi, Ibaraki 305-8585, Japan. satoshi.kubo@jp.astellas.comNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

22041526

Citation

Kubo, Satoshi, et al. "Anti-neutrophilic Inflammatory Activity of ASP3258, a Novel Phosphodiesterase Type 4 Inhibitor." International Immunopharmacology, vol. 12, no. 1, 2012, pp. 59-63.
Kubo S, Kobayashi M, Iwata M, et al. Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor. Int Immunopharmacol. 2012;12(1):59-63.
Kubo, S., Kobayashi, M., Iwata, M., Miyata, K., Takahashi, K., & Shimizu, Y. (2012). Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor. International Immunopharmacology, 12(1), pp. 59-63. doi:10.1016/j.intimp.2011.10.011.
Kubo S, et al. Anti-neutrophilic Inflammatory Activity of ASP3258, a Novel Phosphodiesterase Type 4 Inhibitor. Int Immunopharmacol. 2012;12(1):59-63. PubMed PMID: 22041526.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Anti-neutrophilic inflammatory activity of ASP3258, a novel phosphodiesterase type 4 inhibitor. AU - Kubo,Satoshi, AU - Kobayashi,Miki, AU - Iwata,Masahiro, AU - Miyata,Keiji, AU - Takahashi,Koichiro, AU - Shimizu,Yasuaki, Y1 - 2011/10/29/ PY - 2011/08/26/received PY - 2011/10/12/revised PY - 2011/10/16/accepted PY - 2011/11/2/entrez PY - 2011/11/2/pubmed PY - 2012/5/30/medline SP - 59 EP - 63 JF - International immunopharmacology JO - Int. Immunopharmacol. VL - 12 IS - 1 N2 - Neutrophil-dominant pulmonary inflammation is an important feature of chronic obstructive pulmonary disease (COPD). Here, we evaluated the in vitro and in vivo anti-neutrophilic inflammatory activities of ASP3258, a novel, orally active, and selective phosphodiesterase (PDE) 4 inhibitor with anti-inflammatory potency comparable to that of second-generation compound roflumilast but with lower emetic activity in vivo. In in vitro experiments using human peripheral blood neutrophils, PDE4 inhibitors ASP3258, cilomilast, and roflumilast inhibited fMLP-induced superoxide production in a concentration-dependent manner with IC50 values of 5.0, 96, and 4.7 nM, respectively. ASP3258, cilomilast, and roflumilast also attenuated fMLP-induced neutrophil chemotaxis in a concentration-dependent manner with IC30 values of 18, 270, and 9.7 nM, respectively. In contrast, the glucocorticoid prednisolone inhibited neither superoxide production nor chemotaxis up to 1 μM. In a rat model of lipopolysaccharide (LPS)-induced lung inflammation, orally administered ASP3258, cilomilast, roflumilast, and prednisolone (at 10 or 30 mg/kg) dose-dependently attenuated pulmonary accumulation of neutrophils. The inhibitory effect of ASP3258 was more potent than cilomilast and almost the same as roflumilast and prednisolone. Treatment with ASP3258 inhibited the elevation of TNF-α in the bronchoalveolar lavage fluid following LPS instillation. Histological examination revealed significant inhibition of neutrophil and macrophage infiltration into alveoli by ASP3258. Overall, these findings suggest that ASP3258 has therapeutic potential for treating neutrophilic inflammation such as COPD, partly through direct inhibition of neutrophil activation as well as possibly through inhibition of the TNF-α-mediated pathway. SN - 1878-1705 UR - https://www.unboundmedicine.com/medline/citation/22041526/Anti_neutrophilic_inflammatory_activity_of_ASP3258_a_novel_phosphodiesterase_type_4_inhibitor_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S1567-5769(11)00405-X DB - PRIME DP - Unbound Medicine ER -