Acute respiratory distress syndrome (ARDS) is characterized by the acute onset of bilateral pulmonary infiltrates and severe hypoxemia with respiratory failure, in the absence of cardiogenic pulmonary edema [
1]. The underlying causes of ARDS are various but can be generally divided in two broad categories: a direct pulmonary insult, like a pulmonary infection, or an indirect insult on the lungs, such as sepsis [
2‐
9]. If the etiology of ARDS is restricted to damage or disease of the lung itself, it is called pulmonary ARDS (ARDSp) [
2‐
9]. If the etiology of ARDS occurs outside the lung, as in a systematic inflammatory response, it is called extra-pulmonary ARDS (ARDSexp) [
2‐
9]. Both types of ARDS are characterized by damage of the alveolar-capillary barrier due to diffuse alveolar damage and capillary endothelial injury [
4‐
6]. Studies in humans have reported different pathophysiology, respiratory mechanics and morphological properties between ARDSp and ARDSexp [
3‐
8]. In the early stages of ARDSp, damage to the alveolar cells is prevalent, whereas in ARDSexp, interstitial edema is the first indication of damage [
5]. Furthermore, in broncho-alveolar lung fluid (BALF), the interleukin-8 (IL-8) concentration, a pro-inflammatory cytokine of systemic inflammation and neutrophil recruitment, is significantly higher in ARDSp than in ARDSexp patients [
9].
Different animal models have been used to study the pathophysiology of pulmonary and extra-pulmonary ARDS [
10‐
14]. However, no single animal model mimics all of the clinical features of ARDS seen in humans [
4]. We therefore performed a comparative study in adult sheep, in which ARDS was induced using four different insults. ARDSp was induced by lung lavage, intratracheal administration of albumin 20%, or hydrochloric acid [
10,
12‐
14]. We chose the lung lavage and hydrochloric acid insult as ARDSp models because these are proven models for ARDSp in literature [
10,
12‐
14]. The intratracheal albumin 20% model has been published in neonates as a rescue therapy in meconium aspiration syndrome limiting the effect on the lung and reducing the increase of Interleukin-8 [
15,
16]. But in the pathophysiology of ARDS, protein influx, like albumin, in the alveoli induces serious impairment of alveolar surfactant activity [
17]. These data seem to be contradictive. Therefore, we wanted to investigate the effect of this insult on respiratory, cardiovascular and inflammatory outcomes in a naive adult model. ARDSexp was induced by intravenously administering lipopolysaccharide (LPS iv) from E.coli [
10,
12,
14]. The different insults were chosen to reflect the multiple pathogeneses of ARDS [
10‐
14]. When ARDSp was induced by lung lavage or intratracheal administration of albumin 20%, the washout and/or inactivation of surfactant was considered to be the most important mechanism of injury [
10,
12,
14]. This was in contrast to the intratracheal administration of hydrochloric acid where a direct alveolar damage was induced [
10,
12,
13]. The intravenous LPS administration induced a systemic inflammation with secondary endothelial injury [
10,
12,
14]. We hypothesized that there would be differences in pulmonary, cardiovascular and inflammatory outcomes between the ARDSp and ARDSexp group, due to the different pathophysiology. We therefore assessed oxygenation index (OI) and ventilation efficacy index (VEI) as markers for gas exchange; inflammatory cells, and differentiation in broncho-alveolar lavage fluid (BALF) and interleukin-6 (IL-6) and interleukin-8 (IL-8) in BALF as markers for alveolar inflammation; total protein in BALF as a marker for lung injury and edema; disaturated phospholipids (DSPL) in BALF as a marker for surfactant pool size; lung histology as a marker for atelectasis and overinflation; the lung injury score by Matute-Bello et al. as a marker for lung injury and IL-6 in plasma as markers of systemic inflammation. We studied the animals for 4 h after the pre-defined clinical onset of ARDS.