2. ARDS
The acute respiratory distress syndrome, also called acute lung injury, which is a common cause of respiratory failure in critically ill patients, is defined by the onset of noncardiogenic pulmonary oedema, hypoxemia and need for mechanical ventilation up to 1967(Ashbaugh, Bigelow, Petty & Levine, 1967). Over the last decades, the definition of ARDS becomes mature and forms the Berlin definition (Box 1) in 2012(Ranieri et al., 2012). Considering the ‘sophisticated’ measurements are not available in most developing areas, Riviello, E. D. et al. made up supplement to the Berlin definition, deleted the PEEP requirement and replaced the “PaO2/FiO2 <300 mmHg” to “SpO2/FiO2<315”(Riviello et al., 2016).
The normal lung is a space of carbon dioxide excretion and oxygen intake. This gas transfer function depends on the alveoli structure. The alveolar type I cells cover most of the alveoli have a function of gas transition. Between the alveolar type I cells is the alveolar type II cells which can exclude surfactant, the vital factor of reducing surface tension or enabling the alveoli to remain open and facilitating gas exchange. The alveolar type I and II cells form a tight barrier(Bhattacharya & Matthay, 2013). The alveolar type I and II cells have the capacity to absorb surplus fluid from the air space of alveoli by apical sodium channels and basolateral Na+/K+-ATPase pumps(Matthay, 2014). In normal alveoli, there are macrophages, and they defense for the security of alveoli, which keep the normal function of alveoli.
Nevertheless, the alveolar type I and II cells are damaged in the ARDS, and there is much pulmonary dead space, leading to elevating of minute ventilation(Nuckton et al., 2002; Raurich et al., 2010). The mechanism of ARDS is complicated. Hallmarks of ARDS which has been widely accepted include the pulmonary epithelial cells injury (inflammatory injury and disruption of tight junctions), endothelial disruption and epithelial-endothelial barrier disfunction(Bachofen & Weibel, 1982). On the one hand, the bacterial or viral infection calls direct damage to pulmonary epithelial cells. On the other hand, in the indirect injury of pulmonary epithelial cells, the normal function of pulmonary capillary endothelial permanents is disturbed: the injured epithelial cells recruit neutrophils, macrophages from pulmonary parenchyma into the alveolar cavity, then the leukocytes release mass inflammatory mediators like ILs (IL-6, IL-1β), TNF, and angiopoietin. And they activate the endothelial cells, then permit platelets, erythrocytes and monocytes translate from capillary to alveolar cavity. The platelets and monocytes secrete protease, ROS, NETs. (Matthay, Ware & Zimmerman, 2012), which damage the alveolar epithelial cells once again. With the alveolar-capillary permeability increasing, the red blood cell accumulates to the alveolar and releasing hemoglobin that injured the VE-cadherin between the pulmonary endothelial(Bhattacharya & Matthay, 2013). All the above factors increased permeability to liquid and protein across the lung endothelium. Finally, the alveolar oedema became serious, and the function of alveoli, gas exchange, is destroyed.
There are many factors (pneumonia, toxic inhalation, pancreatitis, aspiration, trauma, sepsis, shock, alcohol, tobacco, high risk surgery, preexisting lung disease, radiation, chemotherapy, etc.)(Yadav, Thompson & Gajic, 2017) for the development of ARDS. After being exposed to one or more risk factors and failed to prevent the progress of ARDS in the very beginning, patients must rely on the ventilator to fulfill their need of oxygen. Even worse, that measures may give a second hit to the injured lung of patients(Wang et al., 2019). Eventually, it harms the brain, heart and has a lifelong term effect on the patients’ life or even cause death.
It has passed nearly sixty years since the ARDS was first clearly defined. These years have witnessed the significant progress in the mechanism and pathophysiology of the ARDS. Lung-protective mechanical ventilation, fluid-restrictive resuscitation strategies, prone positioning, and the promotion of ventilator synchrony through the appropriate use of sedation and paralytic agents have all improved outcomes in ARDS, primarily by preventing further iatrogenic lung injury to an already injured lung(Yadav, Thompson & Gajic, 2017). Despite the management of some patients, the mortality of ARDS remains high. Besides, it failed to unfold any effective pharmacotherapy of ARDS. As the vital role of JAK/STAT in inflammation disease and the outcome of JAK inhibitors in treating the COVID pneumonia recently, JAK/STAT signaling becomes potential target to cure ARDS, and thereby it requires further validation of more clinical and preclinical studies.