ARDS: what experimental models have taught us

Acute respiratory distress syndrome (ARDS) is characterized by severe pulmonary inflammation, increased blood–gas barrier permeability, and hypoxemia, resulting in high mortality rates. Despite extensive research, there is still no specific therapy for ARDS and management remains supportive, mostly in the form of protective mechanical ventilation. These limited therapeutic options result from the complexity of ARDS pathophysiology, which involves multiple, overlapping signaling pathways depending on etiology. ARDS models are important to elucidate the mechanisms underlying pathogenesis, progression, and resolution of this syndrome, as well as to develop therapeutic approaches [1]. This brief review will address the main features of human ARDS that may be modeled experimentally, major current models of ARDS, and what these models have taught us concerning pathophysiology and new therapeutic strategies. An ideal model for ARDS research should reproduce the parameters found in human ARDS. However, since models that perfectly mimic human ARDS are lacking, a committee was organized to determine which features characterize ARDS in animals and identify the optimal methods to assess these features [2]. ARDS triggers are numerous, as are the animal models used to study this syndrome. The many etiologies of ARDS can be broadly classified into two categories: direct insults to the lung epithelium (pulmonary ARDS) and indirect insults to vascular endothelium (extrapulmonary ARDS), determined by an acute systemic inflammatory response [3]. Pulmonary ARDS can be induced experimentally by administration of bacteria or bacterial products such as lipopolysaccharide (LPS), hydrochloric acid or gastric particulates, high inspired fractions of oxygen, depletion of surfactant by repeated saline lavage, induction of ischemia/reperfusion by hilar clamping, or mechanical stretch secondary to injurious mechanical ventilation. Extrapulmonary ARDS can be induced using standard models of sepsis (cecal ligation and puncture [CLP], intravenous administration of bacteria or LPS, mesenteric ischemia/reperfusion), paraquat, and oleic acid. More recently, two-hit models were developed using saline lavage or LPS followed by mechanical ventilation, CLP followed by hemorrhage, or peritoneal sepsis combined with gut ischemia/reperfusion [4] (Table 1). Selection of ARDS models depends on local availability, cost, number of animals (if survival is the study endpoint, rodents are ideal), blood sampling requirements (if multiple samples are needed, large animals should be used), and measurement of inflammatory mediators, receptors, or other proteins (large animals lack specific reagents to measure these parameters).