Functional responses of the pulmonary endothelium to thoracic irradiation in rats: Differential modification by D-penicillamine

• Published in: International journal of radiation oncology, biology, physics Vol. 13; no. 10; pp. 1505 - 1513
• Main Authors: Ward, William F., Molteni, Agostino, Ts'ao, Chung-Hsin, Solliday, Norman H.
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 01.10.1987; Elsevier
• Subjects: Angiotensin converting enzyme; Animals; Biological and medical sciences; Drug toxicity and drugs side effects treatment; Endothelium - drug effects; Endothelium - physiology; Endothelium - radiation effects; Epoprostenol - biosynthesis; Lung - drug effects; Lung - physiology; Lung - radiation effects; Male; Medical sciences; Penicillamine; Penicillamine - pharmacology; Peptidyl-Dipeptidase A - metabolism; Pharmacology. Drug treatments; Plasminogen activator; Plasminogen Activators - metabolism; Prostacyclin; Pulmonary endothelium; Radiation injury; Radiation-Protective Agents - pharmacology; Rats; Thromboxane; Thromboxanes - biosynthesis; Toxicity: respiratory system, ent, stomatology; Pulmonary endothelium; Angiotensin converting enzyme; Radiation injury; Rats; Plasminogen activator; Prostacyclin; Thromboxane; Penicillamine; Vertebrata; Chemotherapy; Experimental disease; Mammalia; Rat; Toxicity; Animal; Lung; Rodentia; Biological marker; Endothelium
• ISSN: 0360-3016; 1879-355X
• DOI: 10.1016/0360-3016(87)90318-X

Male rats were sacrificed 2 or 6 months after a range of single doses of gamma rays (0–30 Gy) to the right hemithorax. Half of each dose group consumed control feed continuously after irradiation, and half consumed feed containing the collagen antagonist D-penicillamine (10 mg/rat/day). Four markers of pulmonary endothelial function were monitored: angiotensin converting enzyme (ACE) activity, plasminogen activator (PLA) activity, and prostacyclin (PGI 2) and thromboxane (TXA 2) production. Bronchoalveolar lavage (BAL) fluid also was obtained from the right lung, and was analyzed for macrophage number, and PG1 2 and TXA 2 concentration. Right lung ACE and PLA activities decreased linearly with increasing dose at both 2 and 6 months postirradiation, and penicillamine had no significant effect on either response. In contrast, PGI 2 and TXA 2 production by the right lung increased linearly with increasing radiation dose at both autopsy times. Penicillamine significantly ameliorated the increase in PGI 2 production at 2 months, and the increase in TXA 2 production at both 2 and 6 months postirradiation. Penicillamine dose-reduction factors (DRF) for PGI 2 and TXA 2 production were 1.3–1.4, and the response curve slope ratios were 1.7–2.5 ( p < 0.05). Penicillamine also ameliorated the dose-dependent increase in TXA 2 concentration in the BAL fluid at 2 months. These data indicate that the four “markers” of radiation-induced pulmonary endothelial dysfunction do not respond identically to penicillamine dose-modification. Of the four markers, TXA 2 production exhibits the most significant and widespread penicillamine sparing. TXA 2 is a potent vasoconstrictor, promoter of platelet aggregation, and mediator of inflammation, and partial prevention of the radiation-induced hyperproduction of this eicosanoid may account in part for penicillamine's therapeutic action in this model.