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J Thorac Cardiovasc Surg 2008;136:1250-1256
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Novel approach with intratracheal administration of microgelatin hydrogel microspheres incorporating basic fibroblast growth factor for rescue of rats with monocrotaline-induced pulmonary hypertension

Keiichi Hirose, MD, PhDa, Akira Marui, MD, PhDb, Yoshio Arai, MD, PhDb, Toshihiro Kushibiki, PhDc, Yu Kimura, MEngc, Hisashi Sakaguchi, MDb, Huang Yuang, MDb, B.I.R. Shyamal Chandra, MDb, Tadashi Ikeda, MD, PhDb, Shigeru Amano, MD, PhDd, Yasuhiko Tabata, PhD, DMSc, Dpharmc, Masashi Komeda, MD, PhDb,*

a Department of Cardiovascular Surgery, Shizuoka Children's Hospital, Shizuoka, Japan
b Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
d Department of Laboratory Science, Kyoto University Graduate School of Medicine, Kyoto, Japan
c Institute for Frontier Medical Sciences, Kyoto University, Kyoto, Japan

Received for publication September 30, 2007; revisions received March 28, 2008; accepted for publication May 9, 2008.

* Address for reprints: Masashi Komeda, MD, PhD, Department of Cardiovascular Surgery, Kyoto University Graduate School of Medicine, 54 Shogoin-Kawara-cho, Sakyo-ku, Kyoto, 606-8507, Japan. (Email: komelab{at}kuhp.kyoto-u.ac.jp).

Objectives: Pulmonary hypertension is a life-threatening disease, and alternative strategies are essential for patients with critical pulmonary hypertension. We developed a new procedure using microgelatin hydrogel microspheres incorporating basic fibroblast growth factor (mGHMs/bFGF) for intratracheal administration and evaluated the effect of a single intratracheal administration of mGHMs/bFGF on rats with monocrotaline-induced pulmonary hypertension.

Methods: Monocrotaline was injected into 54 rats simultaneously with intratracheal administration of plain mGHMs (vehicle group), bFGF in solution form (free-bFGF group), mGHMs/bFGF (mGHMs/bFGF group), and plain saline with subcutaneous injection of saline instead of monocrotaline (control group, n = 18). Three weeks after the administration, 48 rats (n = 12 from each group) were subjected to hemodynamic and histologic evaluations. Survival was assessed in 6 rats of each group 10 weeks after the intratracheal administration.

Results: The mGHMs/bFGF group showed significantly lower right ventricular/left ventricular pressure ratios at 3 weeks than the vehicle and free-bFGF groups (0.35 ± 0.04, 0.54 ± 0.11, 0.58 ± 0.21, and 0.36 ± 0.05 for the control, vehicle, free-bFGF, and mGHMs/bFGF groups, respectively; P < .01). Histologically, the mGHMs/bFGF group had a significantly higher number of vessels (diameter ≥50 µm) than the other groups (5.3 ± 2.6, 4.6 ± 2.8, 7.3 ± 2.5, and 18.9 ± 7.0 vessels/mm2, respectively; P < .01). Ten weeks after the intratracheal administration, 6 (100.0%) rats had survived in the control group, and 1 (16.7%) survived in the vehicle, 0 (0%) in the free-bFGF, and 5 (83.3%) in the mGHMs/bFGF groups (n = 6 each).

Conclusions: A single intratracheal administration of mGHMs/bFGF increased the number of vessels in the lung and ameliorated survival and hemodynamics in rats with monocrotaline-induced pulmonary hypertension.

Abbreviations and Acronyms bFGF = basic fibroblast growth factor; LV = left ventricle; MCT = monocrotaline; mGHM = microgelatin hydrogel microsphere; mGHMs/bFGF = microgelatin hydrogel microspheres incorporating basic fibroblast growth factor; PH = pulmonary hypertension; RV = right ventricle






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