Abstract 3575: Imatinib Mesylate Prevents Monocrotaline-Induced Pulmonary Arterial Hypertension by an Immunomodulatory Mechanism
Purpose: The ability of the tyrosine kinase inhibitor, Gleevec (Imatinib Mesylate, IM), to reverse established pulmonary arterial hypertension (PAH) in animal models has been attributed to inhibition of the PDGF receptor on vascular smooth muscle cells (SMCs). However, IM has also been shown to effectively treat certain forms of cancer by enhancing the anti-tumor capacity of host natural killer (NK) cells. Since the pathogenesis of PAH is characterized by aberrant endothelial and smooth muscle cell proliferation that has been likened to cancer, we hypothesized that the beneficial effects of IM in PAH were related in part to an NK-mediated mechanism.
Methods: Fisher 344 rats, weighing 160 to 180 grams, were given intraperitoneal (i.p.) injections of monocrotaline (MCT, 70 mg/kg). Two weeks after MCT injection, rats began receiving daily i.p. injections of IM (50 mg/kg) or control injections of sterile saline. Animals were randomly assigned to receive intravenous injections of anti-asailo-GM1-enriched rabbit serum (ASGM1) on days 13 and 20 post-MCT to ablate NK cells or an equal volume of heat-inactivated rabbit serum as a control. The onset of PAH was assessed at 28 days after MCT injection by right ventricular systolic pressure (RSVP) and right ventricle hypertrophy as a ratio of right ventricular to left ventricular weight plus septum.
Results: RVSP was elevated in MCT-treated animals (45 ± 2.6 vs. 27 ± 0.5 mmHg no MCT control). The daily administration of IM from days 14 to 28 inhibited the development of PAH (31 ± 1.4 mmHg, p=0.002). Right ventricular hypertrophy was also decreased in IM-treated animals (0.24 ± 0.01) when compared to untreated controls (0.30 ± 0.01, p=0.02). Treatment of rats with ASGM1 completely ablated circulating NK cells, and eliminated the protective effects of IM on both RVSP (41 ± 4.2 mmHg) and RV hypertrophy (0.29 ± 0.02). However, unlike in naíve animals, administration of ASGM1 to MCT-treated rats resulted in the depletion of a large portion of CD4 and CD8 T-cells, in addition to NK cells.
Conclusion: Our results suggest that an immunomodulatory mechanism, as opposed to the PDGFR-mediated effect on vascular SMCs, is the primary mode of action for IM in the MCT rat model.