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Zhang, X.; Su, L.; Pan, P. Basis and Progress in Acute Respiratory Distress Syndrome. Encyclopedia. Available online: (accessed on 21 June 2024).
Zhang X, Su L, Pan P. Basis and Progress in Acute Respiratory Distress Syndrome. Encyclopedia. Available at: Accessed June 21, 2024.
Zhang, Xingwu, Longxiang Su, Pan Pan. "Basis and Progress in Acute Respiratory Distress Syndrome" Encyclopedia, (accessed June 21, 2024).
Zhang, X., Su, L., & Pan, P. (2024, January 26). Basis and Progress in Acute Respiratory Distress Syndrome. In Encyclopedia.
Zhang, Xingwu, et al. "Basis and Progress in Acute Respiratory Distress Syndrome." Encyclopedia. Web. 26 January, 2024.
Basis and Progress in Acute Respiratory Distress Syndrome

Acute Respiratory Distress Syndrome (ARDS) is a sudden onset of lung injury characterized by bilateral pulmonary edema, diffuse inflammation, hypoxemia, and a low P/F ratio. Epithelial injury and endothelial injury are notable in the development of ARDS, which is more severe under mechanical stress.

Acute Respiratory Distress Syndrome (ARDS) lung organoid pluripotent stem cell microfluidic system

1. Introduction

According to the widely-accepted 2012 Berlin definition [1], Acute Respiratory Distress Syndrome (ARDS) is an acute onset of lung injury characterized by bilateral pulmonary edema, diffuse inflammation, hypoxemia with a low P/F ratio, and one exclusion criterion of cardiac causes. Systematic inflammation (non-pneumonia sepsis, pancreatitis, high-risk surgery, and non-cardiogenic shock, etc.) and pulmonary local injury (bacterial, viral, and other atypical types of pneumonia, etc.) are the two major causes of ARDS. High incidence, morbidity, and high medical expenditure make ARDS one of the most prevalent and important complications in the intensive care unit (ICU) [2]. Mortality varies from 34.9% to 46.1% in mild to severe ARDS patients. In addition, as a serious concern in the new era, the COVID-19 pandemic has led to updates in the definition of ARDS, which shows a longer onset of process [3], normal or even high lung compliance [4], and heavier dependence on mechanical ventilation [5].
The central and classic pathological feature of ARDS is diffuse alveolar damage (DAD), which not only is caused by excessive inflammation but is also the reason for diffuse inflammation [6]. Where DAD is concerned, epithelium and endothelium injuries are considered the central processes in pulmonary ARDS and extrapulmonary ARDS, respectively, although it is difficult to differentiate between these two conditions in clinical practice [7][8]. Apart from DAD and systematic inflammation, mechanical stress is a vital factor contributing to the progression of ARDS. While ventilators are acknowledged as life-saving, they can also exacerbate ARDS. Accordingly, several mechanical ventilation approaches have been identified to partly alleviate these adverse effects [9]. However, despite efforts to elucidate its pathophysiological mechanisms, the current understanding of ARDS is incomplete due to the limitations of in vivo and in vitro models.

2. Epithelium Injury in ARDS

It has been proven that alveoli are composed of two types of epithelial cells: type I and type II alveolar epithelial cells (AT1 and AT2 cells) [10][11]. It has long been established that AT2 cells serve as the progenitor of AT1 cells, although recent findings suggest that at least one subtype of AT1 cells (Hopx+Igfbp2) may also have the capacity to trans-differentiate into AT2 cells [12]. Due to their high proliferative capacity, AT2 cells are easier to culture in vitro. In contrast, AT1 cells are not only difficult to maintain in primary culture but also to observe under a light microscope, thereby limiting both explorative and conclusive research on AT1 cells in any kind of lung injury [13][14].
AT1 cells’ primary roles are to facilitate gas exchange, maintain the structural integrity of sacs, and stabilize ion and fluid balance. Furthermore, AT1 cells have also been found to have immunological functions. For example, Yamamoto et al. found AT1 cells as a novel source of CXCL5 after LPS stimulation and upregulation of TLR2 and STING, the latter of which mediates innate immunity for the recognition of bacterial DNA and expression of type I IFNs [15]. Additionally, Lin et al. suggested that the membrane raft structure displayed on AT1 cells is necessary for the passage of paracellular neutrophils into the alveoli [16]. Conversely, AT1 cells can also be the victims of diffuse alveolar injury, with dysfunction correlated with diffuse edema and resultant hypoxemia [17][18].
The basic functions of AT2 cells include producing and secreting surfactant proteins, expression of immunomodulatory proteins, balancing the transepithelial water movement, and replenishment of AT1 cells after injury [14]. In the progression of ARDS, AT2 cells are the central mediators of injury to DAD. Flooding of alveoli due to decreased surfactant phospholipids, as a consequence of IAV infection-induced abnormality of lamellar bodies in AT2 cells, is the primary cause of atelectasis and reduced pulmonary compliance [19][20][21]. Additionally, Interferon-mediated crosstalk between AT2 and AT1 cells initiated by IAV infection leads to degradation and reduction of Na,K-ATPase, which further contributes to edema [22]. Hypercapnia alone in AT2 cells has been identified as an alternative trigger for Na,K-ATPase degradation [23]. ENaC, CFTR, and Na,K-ATPase dysfunction were found to be exclusive to IAV-infected cells rather than uninfected cells, wherein CFTR dysfunction persisted even after the period of infection [24]. In vitro studies using NCI-H441 and A549 cell lines revealed that IAV infection disrupts the epithelial tight junction, thus resulting in edema [25][26]. Nevertheless, considering the proportion of air-contacting area attributed by AT1 cells to alveoli, the disruption of the tight junction might be more relevant in AT1 cells.
Aside from their classical function, fully functional AT2 cells may also hinder the translocation of localized cytokines into circulation. In cases of uncontrolled ARDS, primary damage to injured epithelial cells is amplified via positive-feedback loops mediated by danger-associated molecular patterns (DAMPs) [27]. Interestingly, AT2 cells are also able to produce anticoagulants such as soluble thrombomodulin and endothelial protein C receptor (EPCR) and activate protein C and the anticoagulant pathway. However, pro-inflammatory cytokines can lead to inactivation of TM [28][29], EPCR [30], and tissue factor pathway inhibitor (TFPI) [31] through different mechanisms, which can result in fibrin deposition along the damaged alveolar surface.
After decades of research, many questions related to epithelial cell injury in ARDS have not been fully elucidated, such as the function of AT1 cells and their role in ARDS. Furthermore, there is limited research on the crosstalk between different types of epithelial cells and endothelial cells. It has also been acknowledged that epithelial cell injury can lead to several consequences, including surfactant depletion, diffuse edema, and a pro-coagulant state of local circulation, but little attention has been paid to the causal relationship among these consequences. Understanding the inter-relationship and sequence of different pathophysiological processes in ARDS is of great clinical significance, but research exclusively focusing on one or two cell types is insufficient to provide valuable insight.

3. Endothelium Injury in ARDS

Around 32% of all ARDS cases are derived from sepsis or other extrapulmonary injury, where alveolar damage is frequently driven by endothelial dysfunction and local inflammation [32]. Multiple factors contribute to endothelium damage, including circulating pathogens, the epithelium, and numerous pro-inflammatory cells. During the progression of sepsis, molecules and proteins released from damaged cells during infection and trauma, namely, damage-associated molecular patterns (DAMPs), play a central role in mediating circulating inflammatory factors and diffuse alveolar damage [33]. Sentinel immune cells are activated in DAMPs and produce multiple cytokines, which upregulate adhesion molecules of the endothelium to recruit and activate circulating and migrating neutrophils [34]. In addition, multiple signals lead to neutrophil adherence and inflammation, including circulating pro-inflammatory molecules (platelet-activating factor, angiopoietin 2, tumor necrosis factor, vascular endothelial growth factor, inflammasome product IL-1, and others) inflammatory mediators (interleukin (IL)-1, IL-6, IL-8, tumor necrosis factor-alpha (TNF-α)), death or pyroptosis of alveolar macrophages [35] and degradation of the endothelial glycocalyx [36]. Inflammation mediated by neutrophils is protective against infection but also injurious to bystander tissues through neutrophil extracellular traps (NETs) or other mechanisms [37].
There are also some atypical pathways mediating endothelium damage. For example, cell-free hemoglobin leads to increased paracellular permeability of human pulmonary microvascular endothelial cell monolayers through oxidative effects, which could be partially abrogated by acetaminophen [38]. On the other hand, Hough and his colleagues applied concentrated hydrochloric acid on the alveolar epithelium and generated life-threatening pulmonary edema, which is partially similar to that in typical ARDS. Interestingly, secondary endothelium injuries are not caused by concomitant membranes but by H2O2-mediated epithelial–endothelial paracrine signaling, and the subsequent endothelial cell damage is caused by uncoupling protein 2 (UCP2)-induced mitochondrial depolarization, suggesting UCP2 as a therapeutic target to block secondary damage caused by epithelial–endothelial paracrine signaling [39].
At present, there is already a relatively clear immunological process model of endothelial cell injury in the inflammatory process, including processes mediated by various immune cells and inflammatory mediators. However, endothelium damage in the pulmonary environment still needs further clarification, especially of the following aspects: (1) the cause of endothelial injury due to the interaction between endothelial cells and epithelial cells; (2) the microenvironment effect, including the causes of endothelial injury by a variety of cells and inflammatory mediators in ARDS; (3) the role of endothelial cells in the repair and recovery process of ARDS.

4. Mechanical Injury in ARDS

Ventilators are vital equipment in the treatment of ARDS and could also become a direct cause of ARDS [40]. Volutrauma, barotrauma, atelectotrauma, and biotrauma are the major aspects of injury caused by the ventilator, namely, ventilator-induced lung injury (VILI). Theoretically, high tidal volumes are the direct cause of volutrauma, while barotrauma describes pressure-related lung injury. It was noticed that pulmonary edema caused by volutrauma is not induced in animals with similar pressure but lower tidal volume, indicating an independent source of pulmonary injury [41]. On the other hand, damage caused by cyclical opening and closing of alveoli is called atelectotrauma, and positive end-expiratory pressure (PEEP) is important in preventing this type of mechanical injury, which was reviewed in 1967 by Ashbaugh et al. [42]. Biotrauma is the mediator of not only all kinds of mechanical injury following pulmonary injury but also systematic injury [43][44]. One specific low-stretch ventilation strategy was considered to reduce inflammatory factors, such as IL-1, IL-6, IL-8, and TNFα in both plasma and bronchoalveolar lavage [45][46].
The pathobiology features of VILI and ARDS share many inflammatory processes and pathways, including disruption of endothelial barrier integrity and the resulting alveolar flooding, while existing evidence suggests that loss of endothelial cell function plays a central role in the occurrence and development of VILI [47]. One translational research study carried out on mice suggested that the pulmonary endothelial cell is the most responsive type of cell to high tidal volume ventilation, followed by inflammatory activation and the epithelium and macrophages being significantly distinct from the LPS-induced inflammatory process, regarding the activation of the NF-κB pathway [48]. It is also suggested that activated pulmonary monocytes and macrophages and their secreted growth factors contribute to post-VILI recovery [49].
Currently, studies on VILI in animal models have guided researchers to focus mainly on the mechanical injury to endothelial cells, and some researchers have attempted to use DRD to act on endothelial cells to reduce VILI by regulating microtubule stability [50]. However, there are few studies on the impact of VILI on ventilation and blood flow and limited research on the damage to non-pulmonary organs by inflammatory mediators and inflammatory cells [51]. Due to factors such as economic conditions, individual heterogeneity, and the complexity of gene manipulation, research applied to animal models cannot provide enough information.


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