Update on the Features and Measurements of Experimental Acute Lung Injury in Animals: An Official American Thoracic Society Workshop Report

Abstract

Advancements in methods, technology, and our understanding of the pathobiology of lung injury have created the need to update the definition of experimental acute lung injury (ALI). We queried 50 participants with expertise in ALI and acute respiratory distress syndrome using a Delphi method composed of a series of electronic surveys and a virtual workshop. We propose that ALI presents as a "multidimensional entity" characterized by four "domains" that reflect the key pathophysiologic features and underlying biology of human acute respiratory distress syndrome. These domains are 1) histological evidence of tissue injury, 2) alteration of the alveolar-capillary barrier, 3) presence of an inflammatory response, and 4) physiologic dysfunction. For each domain, we present "relevant measurements," defined as those proposed by at least 30% of respondents. We propose that experimental ALI encompasses a continuum of models ranging from those focusing on gaining specific mechanistic insights to those primarily concerned with preclinical testing of novel therapeutics or interventions. We suggest that mechanistic studies may justifiably focus on a single domain of lung injury, but models must document alterations of at least three of the four domains to qualify as "experimental ALI." Finally, we propose that a time criterion defining "acute" in ALI remains relevant, but the actual time may vary based on the specific model and the aspect of injury being modeled. The continuum concept of ALI increases the flexibility and applicability of the definition to multiple models while increasing the likelihood of translating preclinical findings to critically ill patients.

Keywords: extravascular lung water; hypoxia; lung injury; pneumonia; respiratory distress syndrome.

Figure 1.

Modeling clinical features of ARDS for mechanistic analyses and therapeutic interventions. ARDS = acute respiratory distress syndrome; BP = blood pressure; HR = heart rate; ${\text{Sp}}_{{\text{O}}_{\text{2}}}$ = pulse oximetry.

Figure 2.

Delphi method for determining measurements for experimental acute lung injury (ALI). Schematic representation of the three rounds of the Delphi method used to arrive at the measurements of experimental ALI. Domain X represents any one of the four domains: 1) histologic evidence of injury, 2) disruption of the alveolar–capillary barrier, 3) presence of an inflammatory response, and 4) evidence of physiologic dysfunction. The complete list of questions and their answers is provided in Tables E2–E4, corresponding to each round. The number of respondents in each round have been provided on the right-hand side of the figure. The figure was created using www.biorender.com

Figure 3.

The “continuum” framework. Experimental ALI encompasses a continuum of models ranging from those focusing on the study of basic biology for gaining specific mechanistic insights to those that are largely concerned with preclinical modeling of therapeutics or promising interventions. This new framework acknowledges that mechanistic studies may justifiably focus on one or two domains of lung injury (i.e., “potential lung injury”). However, to fully qualify as “experimental ALI” (i.e., “demonstrated lung injury”), a model should demonstrate alterations in at least three of the four domains, reflecting the multidimensional aspects of human ARDS (Table 1).