Oeckler, Richard A.

In the following perspective, we will highlight seemingly remote, downstream consequences of common ventilator management decisions. For example, a change in PEEP may alter venous return, blood pressure, cardiac output, arterial and venous blood gas tensions, metabolic rate, respiratory sensations, breathing pattern, and the work of breathing. If providers consider any of these changes dangerous or maladaptive, they may initiate additional interventions in the form of vasoactive agents, intravenous fluids, and/or sedatives, all of which have their own risk/benefit profile. The approach to such co-interventions is rarely addressed even in well-designed large clinical trials. Therefore, it is often impossible to infer intervention-specific mechanisms of action and/or identify the phenotype of responders and nonresponders in such trials. On the flip side, in preclinical research intended to uncover mechanisms, experimental animals are rarely treated the way a critically ill patient would be. For respiratory therapists, this knowledge gap stresses the imperative to think beyond the lungs and to communicate ventilator management decisions with all members of the healthcare team.

Once excess liquid gains access to air spaces of an injured lung, the act of breathing creates and destroys foam and thereby contributes to the wounding of epithelial cells by interfacial stress. Since cells are not elastic continua, but rather complex network structures composed of solid as well as liquid elements, we hypothesize that plasma membrane (PM) wounding is preceded by a phase separation, which results in blebbing. We postulate that interventions such as a hypertonic treatment increase adhesive PM-cytoskeletal (CSK) interactions, thereby preventing blebbing as well as PM wounds. We formed PM tethers in alveolar epithelial cells and fibroblasts and measured their retractive force as readout of PM-CSK adhesive interactions using optical tweezers. A 50-mOsm increase in media osmolarity consistently increased the tether retractive force in epithelial cells but lowered it in fibroblasts. The osmo-response was abolished by pretreatment with latrunculin, cytochalasin D, and calcium chelation. Epithelial cells and fibroblasts were exposed to interfacial stress in a microchannel, and the fraction of wounded cells were measured. Interventions that increased PM-CSK adhesive interactions prevented blebbing and were cytoprotective regardless of cell type. Finally, we exposed ex vivo perfused rat lungs to injurious mechanical ventilation and showed that hypertonic conditioning reduced the number of wounded subpleural alveolus resident cells to baseline levels. Our observations support the hypothesis that PM-CSK adhesive interactions are important determinants of the cellular response to deforming stress and pave the way for preclinical efficacy trials of hypertonic treatment in experimental models of acute lung injury.