Solnatide Demonstrates Profound Therapeutic Activity in a Rat Model of Pulmonary Edema Induced by Acute Hypobaric Hypoxia and Exercise

Qiquan Zhou, Dong Wang, Yunsheng Liu, Xiaohong Yang, Rudolf Lucas, Bernhard Fischer

Research output: Contribution to journalArticle

7 Citations (Scopus)

Abstract

Background 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. Methods 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. Results 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. Conclusions 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.

Original languageEnglish (US)
Pages (from-to)658-667
Number of pages10
JournalCHEST
Volume151
Issue number3
DOIs
StatePublished - Mar 1 2017

Fingerprint

Pulmonary Edema
Occludin
Dimercaprol
Aminophylline
Lung
Exercise
Dexamethasone
Therapeutics
Gases
Extravascular Lung Water
Tight Junction Proteins
Epithelial Sodium Channels
Water
p38 Mitogen-Activated Protein Kinases
Protein Kinase Inhibitors
Hypoxia
Sodium Chloride
Sprague Dawley Rats
Reactive Oxygen Species
Immunohistochemistry

Keywords

  • HAPE rat model
  • cytokines
  • dexamethasone
  • high-altitude pulmonary edema
  • inflammation

ASJC Scopus subject areas

  • Pulmonary and Respiratory Medicine
  • Critical Care and Intensive Care Medicine
  • Cardiology and Cardiovascular Medicine

Cite this

Solnatide Demonstrates Profound Therapeutic Activity in a Rat Model of Pulmonary Edema Induced by Acute Hypobaric Hypoxia and Exercise. / Zhou, Qiquan; Wang, Dong; Liu, Yunsheng; Yang, Xiaohong; Lucas, Rudolf; Fischer, Bernhard.

In: CHEST, Vol. 151, No. 3, 01.03.2017, p. 658-667.

Research output: Contribution to journalArticle

Zhou, Qiquan ; Wang, Dong ; Liu, Yunsheng ; Yang, Xiaohong ; Lucas, Rudolf ; Fischer, Bernhard. / Solnatide Demonstrates Profound Therapeutic Activity in a Rat Model of Pulmonary Edema Induced by Acute Hypobaric Hypoxia and Exercise. In: CHEST. 2017 ; Vol. 151, No. 3. pp. 658-667.
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AU - Lucas, Rudolf

AU - Fischer, Bernhard

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AB - Background 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. Methods 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. Results 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. Conclusions 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.

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