Abstract 1945: Novel Approach to Rescue Severe Pulmonary Hypertension (PH) with Intratracheal Administration of Micro Gelatin Hydrogel Microspheres Incorporating Basic Fibroblast Growth Factor (bFGF)
Objective Severe PH is a life-threatening disease which is curable ultimately only by heart-lung transplantation. Angiogenic and arteriogenic properties of bFGF may ameliorate severe PH; however, optimal delivery method to the lung has not been established. Considering clinical settings, we have newly developed sustained-release system of bFGF utilizing micro gelatin hydrogel microspheres (mGM: diameter = 10μm) for intratracheal administration.
Hypothesis Single intratracheal administration of mGM incorporating bFGF (FGF/mGM) may be effective for prevention and treatment of monocrotaline (MCT)-induced PH of rats.
Methods and Results [Prevention of progressive PH] MCT (60 mg/kg) was subcutaneously injected to the rats (n = 36), and they had simultaneous intratracheal administration of: FGF/mGM (Group I), plain mGM (group II), and solution form of bFGF (group III), respectively. Rats in group I showed lower RV to LV pressure ratio at 3 weeks (0.36 ± 0.05 vs. 0.54 ± 0.11 and 0.58 ± 0.21 for groups I, II, and III, respectively; P < 0.01). PaO2 of arterial gas analyzes under mechanical ventilation (FiO2 0.21, respiratory rate 60 breathes /min) of group I was also significantly higher than those of the other groups (97.8 ± 11.2 vs. 79.0 ± 11.1 and 84.5 ± 17.2 mmHg for groups I, II, and III, respectively; P < 0.05). Histologically, the number of arterioles (diameter > 50 μm) per mm2 area of group I was significantly higher than those of the other groups (18.9 ± 7.0 vs. 4.6 ± 2.8 and 7.3 ± 2.5 vessels/mm2 for groups I, II, and III, respectively; P < 0.01). [Treatment of advanced PH] Three weeks after MCT injection, when PH is completed, rats (n = 18) had intratracheal administration of FGF/mGM (group IV), plain mGM (group V), and solution form of bFGF (group VI). Rats in group IV showed lower RV to LV pressure ratio at 3 weeks (0.49 ± 0.14 vs. 0.82 ± 0 and 0.69 ± 0.09 for groups IV, V, and VI, respectively; P < 0.01). Rats in Group IV showed far better survival at 3 weeks (83.3 % vs. 16.7 % and 33.3 % for groups IV, V, and VI, respectively; P < 0.01).
Conclusions Single intratracheal administration of FGF/mGM prevented progression of PH and ameliorated the survival of advanced PH with potential improvement of gas-exchange. This approach may help patients with PH effectively with minimal invasiveness.