Clinical ARDS: Berlin definition and its “limitations”
The acute respiratory distress syndrome (ARDS) represents a critical pulmonary disease entity which is pathophysiologically characterized by pulmonary endothelial injury and alveolar epithelial barrier disruption. In clinical practice intensive care givers use the Berlin definition of ARDS, established in 2012 in order to classify patients into three categories of severity on the basis of the PaO2/FiO2 ratio and other ventilatory parameters [1]. Depending on the degree of disease severity (from “mild” to “severe”) several supportive therapeutic interventions are considered, ranging from protective ventilation to extracorporeal membrane oxygenation (ECMO) [2]. Currently, the Berlin definition does not directly register the underlying pathophysiological mechanisms in ARDS like endothelial barrier dysfunction or altered endothelial cell behavior in the course of the disease [1, 3]. Regarding the development of pathophysiologically driven therapy options an integration of biomarkers for ARDS (like circulating endothelial cells, CECs) into the current clinical classification systems might be necessary.
Translational research in ARDS
With respect to endothelial and alveolar epithelial injury, translational research in ARDS mainly focusses on the interaction between neutrophils, platelets, macrophages, endothelial and alveolar epithelial cells [4]. Based on the vascular/inflammatory basis of ARDS pathophysiology, several treatment options like glucocorticoids, inhaled antioxidants, or protease inhibitors have been tested but lack proven overall effectiveness [5]. Promising new approaches towards the development of pathophysiologically driven therapies are based on cellular therapies such as bone marrow-derived progenitor cells [6, 7]. Considering the importance of endothelial barrier dysfunction in ARDS, current research effort is being put into unveiling new vascular/endothelium-based targeted therapy options in ARDS [8].
Pulmonary endothelium in ARDS
To some extent constitutively but also partly upon exposure to activating stimuli the pulmonary endothelium regulates platelet aggregation, hemofluidity, and the vascular tone, it functions as a physiological barrier, participates in immune reactions, and exerts redox activities [8, 9].
Endothelial cell activation by specific stimuli is a central mechanism in the pathogenesis of ARDS [4]. There are several stimuli that may activate pulmonary endothelial cells (EC) such as mechanical stress or inflammatory cytokines like TNF-α and IL-1. ECs react upon activation with the expression of adhesion molecules (E- and P-selectins as well as ICAM-1 and PECAM-1) in the context of neutrophil recruitment, with the increase of permeability, the promotion of platelet aggregation [8], and with the production of reactive oxygen species (ROS) [10]. In that way a pathophysiologically appropriate degree of EC activation in the course of ARDS may also lead to endothelial cell damage (giving rise to an increase of CEC levels), a situation which is aggravated by the activation of transmigrating neutrophils [8]. Endothelial cell damage is one reason for the increase in endothelial permeability in ARDS leading to alveolar fluid accumulation. This is one reason why current research efforts target on CECs as makers for endothelial damage in the course of EC activation in sepsis and ARDS [3]. Latest perceptions suggest that the serum level of CECs might prove to be a potent surrogate parameter for the severity of ARDS and the prognosis of the suffering patient [3].
Biomarkers for endothelial injury and their clinical significance
Endothelial dysfunction in ARDS leads to shifts in activity or serum levels of endothelial-specific proteins, including angiotensin converting enzyme (ACE) [11], tissue factor pathway inhibitor [12], and von Willebrand factor [13]. Also, levels of endothelial progenitor cells are significantly increased in ARDS and show a correlation with improved survival [14]. In the study by Moussa et al. [3] the counts of CECs were significantly higher in ARDS patients compared to other critically ill patients. Within the ARDS group, patients with moderate and severe ARDS had significantly higher CEC counts on day 1 than patients with milder disease; therefore, the authors suggest CEC to be a useful marker of ARDS severity [3]. It remains to be determined whether CECs are useful as a biomarker of clinical outcome and/or treatment response in ARDS patients.
Endothelial regeneration
Simultaneously with endothelial injury, reconstitution of the endothelial layer is initiated. This reconstitution generally involves two biologic paradigms referred to as angiogenesis and vasculogenesis. Angiogenesis is the formation of new blood vessels via migration and proliferation of the endothelium of pre-existing vessels. The capacity of mature endothelial cells to proliferate, however, depends on the presence of endothelial colony forming cells (ECFC) that give rise to endothelial progeny [15]. Since there might be heterogeneity in the level of proliferative potential depending, e.g., on the vascular bed, adequate vascular repair might require additional support. In this context, adult vasculogenesis—the de novo formation of blood vessels from endothelial progenitor cells (EPC)—has been demonstrated to play a role (Fig. 1) [15]. Both cell types seem to be involved in the repair of endothelial denudation injury. While proangiogenic hematopoietic cells (PHC) are first recruited to the site of injury to facilitate repair, ECFC have vascular-forming ability and integrate into the denuded vasculatures (Fig. 1) [15].
The critical question put forward in all studies involves the role that circulating and resident progenitor cells play in the resolution of injured pulmonary endothelium and increased pulmonary vascular permeability in the course of ARDS. It has been shown that the administration of bone marrow-derived progenitor cells (BMDPCs) decreases both the systemic and local inflammatory responses induced by endotoxin, and is associated with improved clinical outcomes [6, 7]. Therefore, the differential release of progenitor cells from the bone marrow offers particular therapeutic potential. Strategies to manipulate the microenvironment to enhance lung repair, particularly in patients who are immunocompromised and have inadequate bone marrow responses, would provide obvious therapeutic benefits. The particular BMDPC populations that are critical in repairing lung injuries remain to be determined. This could lead to important approaches in cell-based treatments where effective BMDPCs are infused in patients with ARDS and other lung diseases.
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Patry, C., Orfanos, S.E. & Rafat, N. Translational research in ARDS patients: new biological phenotypes. Intensive Care Med 41, 1986–1989 (2015). https://doi.org/10.1007/s00134-015-4005-9
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DOI: https://doi.org/10.1007/s00134-015-4005-9