Pulmonary Eosinophilia in a Murine Model of Allergic Inflammation Is Attenuated by Small Molecule α4β1 Antagonists

Abstract

Inhibition of ␣4␤1/vascular cell adhesion molecule-1 (VCAM-1) interactions have therapeutic potential in treating allergic airway disease because of the importance of these adhesion molecules in the trafficking of eosinophils, lymphocytes, and monocytes. We examined several small molecule inhibitors of ␣4␤1/VCAM-1 interactions with in vitro potencies (IC 50 values) ranging from 0.52 nM (CP-664511; 3-The same compounds were evaluated in vivo using a murine model of ovalbumin-induced pulmonary eosinophilia. In this model, systemic administration of antibodies against ␣4 reduced bronchoalveolar lavage (BAL) eosinophilia ϳ60%. Small molecule ␣4␤1 antagonists were administered by intratracheal instillation and demonstrated dose-dependent inhibition of BAL eosinophil numbers and achieved a maximum inhibition of ϳ60%. In general, the rank order of potency for these compounds in vitro was consistent with that observed in vivo, which confirms that their efficacy is likely via blockade of ␣4␤1/VCAM-1 interactions. The most potent compound, CP-664511, also inhibited BAL eosinophilia following s.c. administration (1-10 mg/kg, s.c.). These data support the utility of small molecule ␣4␤1 antagonists in the treatment of relevant diseases, such as asthma.

Unconjugated Bilirubin Inhibits VCAM-1-Mediated Transendothelial Leukocyte Migration

“…administration of bilirubin blocks the influx of leukocytes into the lungs of mice with OVA-induced asthma. It has previously been shown that Abs to ␣ 4 integrins or VCAM-1 inhibit the recruitment of eosinophils and lymphocytes into the airways of OVA-sensitized and OVA-challenged mice (34,35). Our finding that bilirubin treatment has identical effects on OVA-induced leukocyte recruitment is consistent with a mechanism of action that involves the disruption of VCAM-1 signaling.…”

“…10). Because, in this model, both eosinophil and lymphocyte migration into the lungs have been shown to be VCAM-1-dependent (34,35), our data are consistent with the hypothesis that bilirubin blocks pulmonary leukocyte infiltration by inhibiting VCAM-1 signaling.…”

“…Subsequent exposure of sensitized animals to intranasal OVA produces an asthma-like Th2 immune response. The resultant pulmonary eosinophilia and lymphocytosis has previously been demonstrated to be VCAM-1-dependent (34,35). Following intranasal OVA challenge, mice were administered a total of six doses of bilirubin (30 mg/kg), or potassium phosphate vehicle, i.p.…”

“…To evaluate whether bilirubin is able to inhibit VCAM-1-mediated leukocyte migration in vivo, we used a murine model of OVAinduced airway inflammation (34,35). C57BL6/J mice were administered OVA via i.p.…”

A Small Molecule α4β1 Antagonist Prevents Development of Murine Lyme Arthritis without Affecting Protective Immunity

“…To date, targeting of ␣ 4 ␤ 1 with synthetic antagonists has been examined in mouse models of lung inflammation/asthma (43,44) and experimental autoimmune encephalomyelitis/MS (45,46) with predominantly beneficial results. However, to our knowledge, no small molecule antagonists specific to ␣ 4 ␤ 1 have been tested so far for treatment in an animal model of an infectious disease.…”