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Attenuation of lung ischemia-reperfusion injury by rho-associated kinase inhibition in a rat model of lung transplantation.

AbstractBACKGROUND:
A signaling pathway of the small GTPase Rho and Rho-associated coiled-coil-forming protein kinase (ROCK), regulates the contraction of endothelial cells. We studied the effects of Y-27632, a specific ROCK inhibitor, to clarify the role of Rho/ROCK in the pathogenesis of ischemia-reperfusion lung injury in a rat model of single-lung transplantation (LTX).
METHODS:
We flushed 5 donor rat lungs with Euro-Collins solution, and 5 donor lungs with Euro-Collins + Y-27632, 0.03 mg/ml, and preserved the lungs for 6 h at 4°C before reperfusion for 4 h. The 5 rat recipients of Y-27632-treated lungs also received a 10-mg/kg bolus of Y-27632 i.p. 30 min before reperfusion.
RESULTS:
Pretreatment of the donor lungs and recipient rats with Y-27632 prominently suppressed the post-LTX edema, while the permeability index was only slightly decreased. The (1) numbers of neutrophils and macrophages, and (2) tumor necrosis factor (TNF)-α concentration, were significantly lower in the bronchoalveolar lavage fluid of treated than untreated lungs.
CONCLUSIONS:
Y-27632 (1) inhibited the migration of inflammatory cells into the alveolar space, (2) decreased the production of TNF-α, and (3) attenuated the edema after LTX. Endothelial Rho and ROCK may play an important role in the pathogenesis of post-LTX injury.
AuthorsMitsutomo Kohno, Masazumi Watanabe, Taichiro Goto, Ikuo Kamiyama, Takashi Ohtsuka, Sadatomo Tasaka, Makoto Sawafuji
JournalAnnals of thoracic and cardiovascular surgery : official journal of the Association of Thoracic and Cardiovascular Surgeons of Asia (Ann Thorac Cardiovasc Surg) Vol. 20 Issue 5 Pg. 359-64 ( 2014) ISSN: 2186-1005 [Electronic] Japan
PMID24088927 (Publication Type: Journal Article)
Chemical References
  • Amides
  • Protein Kinase Inhibitors
  • Pyridines
  • Tumor Necrosis Factor-alpha
  • Y 27632
  • rho-Associated Kinases
Topics
  • Amides (pharmacology)
  • Animals
  • Bronchoalveolar Lavage Fluid (cytology, immunology)
  • Chemotaxis (drug effects)
  • Cytoprotection
  • Disease Models, Animal
  • Lung (drug effects, enzymology, immunology)
  • Lung Injury (enzymology, etiology, immunology, prevention & control)
  • Lung Transplantation (adverse effects)
  • Macrophages (drug effects, immunology)
  • Neutrophil Infiltration (drug effects)
  • Permeability
  • Protein Kinase Inhibitors (pharmacology)
  • Pulmonary Edema (enzymology, prevention & control)
  • Pyridines (pharmacology)
  • Rats, Inbred Lew
  • Reperfusion Injury (enzymology, etiology, immunology, prevention & control)
  • Signal Transduction (drug effects)
  • Time Factors
  • Tumor Necrosis Factor-alpha (metabolism)
  • rho-Associated Kinases (antagonists & inhibitors, metabolism)

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