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.