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).
What have animal models taught us?
Pathophysiology
ARDS pathophysiology is complex and involves multiple molecular, cellular, and physiological mechanisms, which hinders organization of these factors into a single pathogenetic pathway. Alveolar macrophages participate by orchestrating the inflammatory process, recruiting neutrophils and circulating macrophages to the site of lung damage [5]. Neutrophil extracellular traps (NETs), which are found in different ARDS models (e.g., endotoxin, influenza), are produced by neutrophils to trap bacterial, fungal, and viral pathogens [6]. These cells release cytokines, proteases, reactive oxygen species, eicosanoids, and phospholipids, thus perpetuating the inflammatory response and damaging epithelial and endothelial cells. Type II epithelial cell damage reduces surfactant production and disrupts normal fluid transport, impairing edema resolution, while endothelial cell injury increases vascular permeability, leading to edema formation.
New aspects of ARDS pathophysiology
Both the development and resolution of ARDS seem to be related to toll-like receptor (TLR) signaling pathways. TLRs are transmembrane proteins that recognize pathogen-associated molecular patterns (PAMPs) (bacterial cell wall components) and damage-associated molecular pattern (DAMPs) (intracellular proteins, namely heat shock proteins and extracellular matrix fragments) [5]. Stimulation of TLRs by PAMPs or DAMPs leads to activation of transcription factors (e.g., AP-1, NF-κB) and production of mediators. Nucleotide-binding oligomerization domain-like receptors (NLRs) are cytosolic receptors that respond to different PAMPs and DAMPs and are responsible for the sterile inflammation response. ARDS is also characterized by activation of the ubiquitin–proteasome system, increasing expression of ubiquitin within type II epithelial cells. Despite substantial progress, further experimental studies are required to elucidate the aforementioned mechanisms and help design future ARDS therapies.
Potential new therapeutic targets in ARDS
Different therapies have been tested in animals before clinical studies. The challenge is to extrapolate the data obtained from animal studies to human patients.
Several anti-inflammatory agents have failed to show any mortality benefit in ARDS. Inhaled corticosteroids, angiotensin-converting enzyme inhibitors, peroxisome-proliferator receptor agonists, tyrosine kinase inhibitors [7], proteasomes, and inflammasomes have been studied in experimental ARDS. Various new approaches aim to repair the endothelium. FG-4497 has been shown to support the integrity of adherens junctions, thus preventing loss of endothelial barrier function [8]. Mesenchymal stromal cells (MSCs) are also effective in experimental ARDS, as they secrete paracrine factors that regulate alveolar-capillary permeability and reduce inflammation, fibrosis, and infection in experimental ARDS [9]. Gene therapy aiming to increase expression of the ion channels and pumps required for alveolar fluid clearance is another possible future therapy [10]. Use of low tidal volumes (V T) improves survival in ARDS, but V T itself does not seem to play an important role in ventilator-associated lung injury (VALI), unlike driving pressure, for which there is no safe limit. As VALI is an important cause of poor clinical outcomes in ARDS patients, strategies that reduce its incidence and severity are being sought. Variable ventilation, management of spontaneous breathing, and different recruitment maneuver techniques have been evaluated in experimental ARDS [11–13]. Additionally, evaluation of transpulmonary pressure will provide a new approach to mechanical ventilation settings [14].
Summary
Improving the course and outcome of patients with ARDS presents a considerable challenge. Animal studies attempting to mimic human ARDS have been useful and will continue to provide valuable insight into both the mechanisms underlying pathogenesis, progression, and resolution of this syndrome and ways in which its course can be modulated therapeutically. Unbiased methodologies, including metabolomics, proteomics, gene expression analysis, and genome-wide association studies, have the potential to identify new mediators and pathways that are mechanistically important. Although no single model perfectly resembles human ARDS, the best model is that which best addresses researchers’ experimental issues and can simulate all adjuvant therapies used in the ICU. The most exciting current treatment strategy is to reduce ARDS incidence with preemptive application of protective mechanical ventilation to patients at high risk of developing ARDS.
References
Rocco PR, Zin WA (2002) Experimental models of acute lung injury. In: Gullo A (ed) Anaesthesia, pain, intensive care and emergency medicine (A.P.I.C.E.). Springer, Milan, pp 175–191
Matute-Bello G, Downey G, Moore BB, Groshong SD, Matthay MA, Slutsky AS, Kuebler WM, Acute Lung Injury in Animals Study Group (2011) An official American Thoracic Society workshop report: features and measurements of experimental acute lung injury in animals. Am J Respir Cell Mol Biol 44:725–738
Rocco PR, Pelosi P (2008) Pulmonary and extrapulmonary acute respiratory distress syndrome: myth or reality? Curr Opin Crit Care 14:50–58
Kollisch-Singule M, Emr B, Jain SV, Andrews P, Satalin J, Liu J, Porcellio E, Kenyon V, Wang G, Marx W, Gatto LA, Nieman GF, Habashi NM (2015) The effects of airway pressure release ventilation on respiratory mechanics in extrapulmonary lung injury. Intensive Care Med Exp 3:35
Han S, Mallampalli RK (2015) The acute respiratory distress syndrome: from mechanism to translation. J Immunol 194:855–860
Bosmann M, Ward PA (2014) Protein-based therapies for acute lung injury: targeting neutrophil extracellular traps. Expert Opin Ther Targ 18:703–714
Oliveira GP, Silva JD, Marques PS, Gonçalves-de-Albuquerque CF, Santos HL, Vascocellos AP, Takiya CM, Morales MM, Pelosi P, Mócsai A, de Castro-Faria-Neto HC, Rocco PR (2015) The effects of dasatinib in experimental acute respiratory distress syndrome depend on dose and etiology. Cell Physiol Biochem 36:1644–1658
Silva PL, Rocco PR, Pelosi P (2015) FG-4497: a new target for acute respiratory distress syndrome? Expert Rev Respir Med 9:405–409
Antunes MA, Laffey JG, Pelosi P, Rocco PR (2014) Mesenchymal stem cell trials for pulmonary diseases. J Cell Biochem 115:1023–1032
Devaney J, Contreras M, Laffey JG (2011) Clinical review: gene-based therapies for ALI/ARDS: where are we now? Crit Care 15:224
Saddy F, Sutherasan Y, Rocco PR, Pelosi P (2014) Ventilator-associated lung injury during assisted mechanical ventilation. Semin Respir Crit Care Med 35:409–417
Roy S, Habashi N, Sadowitz B, Andrews P, Ge L, Wang G, Roy P, Ghosh A, Kuhn M, Satalin J, Gatto LA, Lin X, Dean DA, Vodovotz Y, Nieman G (2013) Early airway pressure release ventilation prevents ARDS-a novel preventive approach to lung injury. Shock 39:28–38
Silva PL, Moraes L, Santos RS, Samary C, Ornellas DS, Maron-Gutierrez T, Morales MM, Saddy F, Capelozzi VL, Pelosi P, Marini JJ, Gama de Abreu M, Rocco PR (2011) Impact of pressure profile and duration of recruitment maneuvers on morphofunctional and biochemical variables in experimental lung injury. Crit Care Med 39:1074–1081
Samary CS, Santos RS, Santos CL, Felix NS, Bentes M, Barboza T, Capelozzi VL, Morales MM, Garcia CS, Souza SA, Marini JJ, Gama de Abreu M, Silva PL, Pelosi P, Rocco PR (2015) Biological impact of transpulmonary driving pressure in experimental acute respiratory distress syndrome. Anesthesiology 123:423–433
Acknowledgments
The authors would like to express their gratitude to Mrs. Moira Elizabeth Schottler and Mr. Filippe Vasconcellos for their assistance in editing the article. This study was supported by the Brazilian Council for Scientific and Technological Development (CNPq), the Rio de Janeiro State Research Foundation (FAPERJ), the Coordination for the Improvement of Higher Education Personnel (CAPES), and the Department of Science and Technology–Brazilian Ministry of Health (DECIT/MS).
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Rocco, P.R.M., Nieman, G.F. ARDS: what experimental models have taught us. Intensive Care Med 42, 806–810 (2016). https://doi.org/10.1007/s00134-016-4268-9
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DOI: https://doi.org/10.1007/s00134-016-4268-9