Fig. 1

Schematic representation of the pathologic tetrad of the acute respiratory distress syndrome (ARDS). The diagram depicts multiple alveolar walls containing pulmonary capillaries (red circles), the alveolar walls are lined with a liquid hypophase (blue layer inside each alveolus), with pulmonary surfactant forming a complete monolayer on the hypophase. Severe trauma, hemorrhagic shock, or sepsis can cause the systemic inflammatory response syndrome (SIRS) that increases permeability of the pulmonary vasculature. (Endothelial Leakage) Increased microvascular permeability allows pulmonary edema to move into the alveolus, initially as individual blebs (increased permeability - arrows and edema blebs in tan color) [70]. (Surfactant Deactivation) Pulmonary surfactant molecules remain in a continuous layer initially as the edema blebs form but as the blebs expand the monolayer is disrupted leading to surfactant deactivation. (Alveolar Edema) A combination of the edema usurping surfactant from the hypophase, the proteins in the edema fluid deactivating surfactant [71], and improper mechanical ventilation [4] causing further surfactant disruption, leads to the destruction of the surfactant monolayer (Surfactant Deactivation). Loss of this monolayer results in increased alveolar surface tension causing the alveoli to become unstable and collapse at expiration (Recruitment/Derecruitment (R/D)). In addition high surface tension has been shown to increase edema flooding of the alveoli setting up a viscous cycle of edema→surfactant deactivation→high alveolar surface tension→more edema [72]. If this viscous cycle is not blocked eventually the alveolar edema will flood the entire alveolus (tan color) preventing gas exchange, leading to hypoxemia and CO₂ retention. A hallmark of ARDS pathophysiology is heterogeneous injury with edema-filled (tan color) adjacent to air-filled alveoli with normal surfactant function (Alveolar Edema). Edema adjacent to air-filled alveoli create a stress-riser causing the alveolar wall to bend toward the fluid filled alveolus, which can cause stress-failure at the alveolar wall [32]. (Green Arrow-Alveolar Edema) Stress-risers are a key mechanism of ventilator-induced lung injury (VILI) [30,31,32,33]. Loss of surfactant function renders the alveoli unstable such that they recruit and derecruit (R/D) with each breath. The alveoli in the top frame of R/D are fully inflated but collapse during expiration in the bottom R/D frame. Alveolar R/D is another key mechanism of VILI and is known as atelectrauma [38]