Date Published: March 23, 2017
Publisher: Public Library of Science
Author(s): Chaomin Wu, Colin E. Evans, Zhiyu Dai, Xiaojia Huang, Xianming Zhang, Hua Jin, Guochang Hu, Yuanlin Song, You-Yang Zhao, Xiao Su.
Acute respiratory distress syndrome (ARDS) is characterized by acute hypoxemia respiratory failure, bilateral pulmonary infiltrates, and pulmonary edema of non-cardiac origin. Effective treatments for ARDS patients may arise from experimental studies with translational mouse models of this disease that aim to delineate the mechanisms underlying the disease pathogenesis. Mouse models of ARDS, however, can be limited by their rapid progression from injured to recovery state, which is in contrast to the course of ARDS in humans. Furthermore, current mouse models of ARDS do not recapitulate certain prominent aspects of the pathogenesis of ARDS in humans. In this study, we developed an improved endotoxemic mouse model of ARDS resembling many features of clinical ARDS including extended courses of injury and recovery as well as development of fibrosis following i.p. injection of lipopolysaccharide (LPS) to corn oil-preloaded mice. Compared with mice receiving LPS alone, those receiving corn oil and LPS exhibited extended course of lung injury and repair that occurred over a period of >2 weeks instead of 3–5days. Importantly, LPS challenge of corn oil-preloaded mice resulted in pulmonary fibrosis during the repair phase as often seen in ARDS patients. In summary, this simple novel mouse model of ARDS could represent a valuable experimental tool to elucidate mechanisms that regulate lung injury and repair in ARDS patients.
Acute respiratory distress syndrome (ARDS) remains a major cause of mortality in intensive care units worldwide [1–3]. The triggers of ARDS can be classified as direct (e.g. pneumonia, inhalation injury, aspiration of gastric contents, pulmonary contusion, or reperfusion pulmonary edema) or indirect (e.g. sepsis, burn, major trauma with shock, multiple blood transfusions, or acute pancreatitis) [1, 2, 4]. ARDS in humans is defined by a list of clinical parameters including diffuse alveolar damage and reduced pulmonary oxygenation [1, 2, 5, 6]. Human ARDS develops over a ≤7day period; in this time frame, the initial exudative/inflammatory stage is followed by a proliferative tissue repair stage; and after 3 weeks, the repair phase can culminate in pulmonary fibrosis (i.e. in two-thirds of ARDS patients) [7–9]. Although the incidence and mortality of ARDS has declined over recent years [3, 10], the mechanisms that regulate the pathogenesis and resolution of ARDS are incompletely understood, and there are still no effective pharmacological or cell-based treatments for this disease.
Here we introduce a modified version of the conventional LPS-induced mouse model of ARDS that induces extended phases of post-sepsis injury and repair along with development of pulmonary fibrosis during the extended recovery phase as seen in ARDS patients. In mice pre-administered with corn oil, LPS-induced inflammatory lung injury peaked at 72 hours post-challenge and did not completely resolve until day 17–20 post-challenge. This extended course of lung repair resembles more closely the course of ARDS recovery in patients, which normally takes 2–4 weeks. Translational mouse models that better replicate the complex pathobiology of ARDS in man could lead to the identification of pathways that regulate human lung injury and subsequent repair, which could in turn be targeted for potential clinical benefit.