1. Introduction
The acute respiratory distress syndrome (ARDS) is a serious respiratory
failure caused by many factors including pneumonia, sepsis, aspiration
of gastric contents or severe trauma which had a high mortality of up to
30-40% in most studies(Rubenfeld et al., 2005). With the outbreak of
COVID-19, COVID-19 related ARDS induced higher fatality rates, and
becomes a public health dilemma
worldwide. Despite various studies in recent years, there is no
effective pharmacotherapeutic agent emerging for the treatment of ARDS.
Besides, decades of research still failed to find any effective
therapies to reduce the mortality in established ARDS(Yadav, Thompson &
Gajic, 2017).
Janus kinase (JAK) is vital transducer of many cytokines’ intracellular
signaling and involved in cell growth, survival, development, and
differentiation of a variety of cells especially immune and
hematopoietic cells(Ghoreschi, Laurence & O’Shea, 2009). There are 4
family members of Janus kinase, Jak1, Jak2, Jak3, and Tyk2. The signal
transducer and activator of transcription family (STAT) is the most
important transducer downstream of the JAKs. Type I and II cytokines
binds to receptors, leading to the dimerization of the receptors, making
the JAKs phosphate themselves, so leaving a docking site to the STATs.
Then STATs are activated, translocated to the nucleus, and elicited
specific transcriptional responses(Buchert, Burns & Ernst, 2016).
Cytokines related in the Janus kinase/signal transducer and activator of
transcription pathway (JAK/STAT) signaling range from growth hormone,
leptin, erythropoietin to ILs, and IFN. JAK/STAT signaling participates
in proinflammatory machinery of the cellular immune response,
heterochromatin stability. Since the first JAK2 inhibitor (ruxolitinib)
approved for treating myelofibrosis by FDA at 2011, JAK inhibitors are
making a brilliant figure in treating inflammation/autoimmune disease,
metabolic homeostasis, tumor progression(Dodington, Desai & Woo, 2018).
As the outcome of JAK inhibitors in treating the COVID pneumonia
recently(Guimaraes et al., 2021), JAK/STAT signaling becomes potential
targets to cure ARDS, but it requires further validation of preclinical
and clinical studies. Here, we review the pathogenesis of ARDS, JAK/STAT
signaling in pulmonary physiology and pathology, JAK inhibitors of
treating ARDS, and therapeutic agents based on JAK/STAT signaling for
ARDS. We also discuss the future trends/strategies in JAK inhibitor
design and usage in ARDS.