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.