Solnatide Demonstrates Profound Therapeutic Activity in a Rat Model of Pulmonary Edema Induced by Acute Hypobaric Hypoxia and Exercise.
The synthetic peptide solnatide is a novel pharmacologic agent that reduces extravascular lung water, blunts reactive oxygen species production, and improves lung function due to its ability to directly activate the epithelial sodium channel. The goal of this study was to investigate the effect of solnatide in pulmonary edema induced by acute hypobaric hypoxia and exercise in rats, which is considered a model for high-altitude pulmonary edema.



Sprague-Dawley rats were assigned to low-altitude control and eight treatment groups. Animals of all groups were subjected to exhaustive exercise in a hypobaric hypoxic environment simulating an altitude of 4,500 meters, followed by simulated ascent to 6,000 meters. After 48 h at 6,000 meters, rats were given sodium chloride, dexamethasone, aminophylline, p38 mitogen activated protein kinase inhibitor, and NOD-like receptor containing a pyrin domain 3 inhibitor, or one of three different doses of solnatide, once daily for 3 consecutive days. After 3 days, arterial blood gas, BAL fluid, lung water content, and histologic and ultra-microstructure analyses were performed. Tight junction protein occludin was assayed by using immunohistochemistry.



Rats treated with solnatide had significantly lower BAL fluid protein and lung water content than high-altitude control rats. Lungs of solnatide-treated rats were intact and showed less hemorrhage and disruption of the alveolar-capillary barrier than those of high-altitude control animals. Occludin expression was significantly higher in solnatide-treated animals, compared with high-altitude control, dexamethasone-, and aminophylline-treated animals.



Solnatide reduced pulmonary edema, increased occludin expression, and improved gas-blood barrier function during acute hypobaric hypoxia and exercise in rats. These results provide a rationale for the clinical application of solnatide to patients with pulmonary edema and exposure to a high-altitude hypoxic environment.
Department of High Altitude Geographical and High Altitude Disease, College of High Altitude Military Medicine, Third Military Medical University, and Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing, China.
Qiquan
Q
Zhou
Department of High Altitude Geographical and High Altitude Disease, College of High Altitude Military Medicine, Third Military Medical University, and Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing, China.
Dong
D
Wang
Department of High Altitude Geographical and High Altitude Disease, College of High Altitude Military Medicine, Third Military Medical University, and Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing, China.
Yunsheng
Y
Liu
Department of High Altitude Geographical and High Altitude Disease, College of High Altitude Military Medicine, Third Military Medical University, and Key Laboratory of High Altitude Medicine, Ministry of Education, Chongqing, China.
Xiaohong
X
Yang
Vascular Biology Center, Division of Pulmonary Medicine, Medical College of Georgia, Augusta University, GA.
Rudolf
R
Lucas
APEPTICO Research and Development, Vienna, Austria. Electronic address: b.fischer@apeptico.com.
Bernhard
B
Fischer
D000532:Altitude Sickness / Q000378:metabolism* / Q000473:pathology; D000628:Aminophylline / Q000494:pharmacology; D000818:Animals; D001784:Blood Gas Analysis; D001992:Bronchoalveolar Lavage Fluid; D001993:Bronchodilator Agents / Q000494:pharmacology; D002196:Capillaries / Q000648:ultrastructure; D003907:Dexamethasone / Q000494:pharmacology; D015633:Extravascular Lung Water / Q000187:drug effects*; D005938:Glucocorticoids / Q000494:pharmacology; D006470:Hemorrhage; D006976:Hypertension, Pulmonary / Q000378:metabolism* / Q000473:pathology; D007150:Immunohistochemistry; D008168:Lung / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000648:ultrastructure; D008854:Microscopy, Electron; D062793:Occludin / Q000187:drug effects / Q000378:metabolism; D010456:Peptides, Cyclic / Q000494:pharmacology*; D010805:Physical Conditioning, Animal; D011650:Pulmonary Alveoli / Q000648:ultrastructure; D011654:Pulmonary Edema / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley
D001993:Bronchodilator Agents; D005938:Glucocorticoids; D062793:Occludin; C568987:Ocln protein, rat; D010456:Peptides, Cyclic; C583752:AP301 peptide; D000628:Aminophylline; D003907:Dexamethasone
HAPE rat model; cytokines; dexamethasone; high-altitude pulmonary edema; inflammation