3.3.1 JAK-STAT related cytokine release and immune response
IL-6 is a vital factor in ARDS which relays on JAK/STAT transfer the
signaling. IL-6 related JAK-STAT activation has a negative impact on the
disease progression of ARDS (caused by tobacco, ventilator, etc.). In
the VILI (ventilator-induced lung injury), intratracheal IL-6
administration in C57BL/6J mice increased protein content and cell count
in bronchoalveolar lavage fluid, which was associated with activation of
JAK signal transducers, activators of transcription, p38 MAP kinase, and
NF-κB signaling(Birukova, Tian, Meliton, Leff, Wu & Birukov, 2012).
Moreover, IL-6 can enlarge the endothelial cell (EC) permeability in the
situation of pathologically relevant cyclic stretch (CS) magnitudes,
increase ICAM-1 expression of pulmonary EC and neutrophil adhesion.
However, Rho kinase inhibitor Y-27632 suppressed the synergistic effect.
That is evidence of Rho taking part in the endothelial
integrity(Gudipaty & Rosenblatt, 2017). Other study also shows that
influenza A virus infection induced muscle wasting via IL-6 regulation
of the E3 ubiquitin ligase atrogin-1(Radigan et al., 2019).
Glucocorticoids like betamethasone (BTM) and dexamethasone (DXM),
potentiate IL-6-induced SP-B expression in H441 cells by enhancing the
JAK-STAT signaling pathway, so make a negative impact on
ARDS(Ladenburger et al., 2010a).
In the mouse model of severe influenza A pneumonia, IL-6 promoted muscle
degradation via the E3 Ubiquitin Ligase atrogin-1, STAT3, FOXO3a(Shaikh,
Bhat & Bhandary, 2020). There is also study shows that glucocorticoids
potentiate IL-6-induced SP-B expression in H441 cells by enhancing the
JAK-STAT signaling pathway and that phenomenon is reversed by JAK1
inhibitor(Ladenburger et al., 2010b). Not only IL-6, there are many
other cytokines, like IL-17A participated in the in vivo mice model of
ALI, may related to ARDS(Shaikh, Bhat & Bhandary, 2020).
As to STAT (1/3) is activated in ARDS, targeting STAT3 may be
therapeutical to ALI and ARDS patients(Severgnini et al., 2004). In
LPS-induced ALI mouse model STAT3 was activated in CD45+CD11b+ cells
from BALF and in LPS treated macrophages in vitro. STAT3 inhibitor LLL12
decreased IL-1β, IL-6, TNF-α, iNOS, CCL2, and MHC class II in
macrophages and inflammatory cells from BALF and serum determined by
ELISA. Hyperactivation of STAT3 in LysMCre-SOCS3fl/fl mice accelerated
the severity of inflammation in the ALI model(Zhao et al., 2016).
Myeloid, Ly6C (+) macrophage, lack of SOCS3 resulted in more expression
of STAT3 and increased LPS-induced murine acute lung injury(Jiang, Chen,
Li, Zhou & Zhu, 2017).
In recent research about alveolar macrophage transcriptional program in
patients, cell-specific AM (alveolar macrophage) proinflammatory and
M1-like(IL-6/JAK/STAT5 activation) at the time of ARDS onset were
associated with better clinical outcomes(Morrell et al., 2019).
Decreasing of p-JAK1, p-STAT1, p-STAT3, and PKM2-mediated glycolytic
pathways could reverse lipopolysaccharide-induced inflammatory responses
of macrophages(Ying, Li, Yu & Yu, 2021). Not only macrophages, there
was also study about the mesenchymal stem cells (MSCs). They affected
ARDS in newborn swine via JAK-STAT signaling pathway. MSCs increased
interleukins (IL-2, IL-6, IL-8), and tumor necrosis factor-α (TNF-α)
expression levels and decreased IL-10 and IL-13.
3.3.2 JAK-STAT in epithelial
function/ smooth muscle
proliferation and surplus fluid absorption
JAK is vital for the epithelial functions. JAK3 was found interacts with
cytoskeletal proteins so play an essential role in cytoskeletal
remodeling and epithelial wound repair(Kumar, Mishra, Narang & Waters,
2007). In mucosal homeostasis, JAK3 interacted with adapter protein
p52ShcA and regulated the expression of differentiation markers,
formation of mucus in mice, and facilitated barrier functions through
its interactions and adherent junction (AJ) localization. In DSS mouse
model, knockdown of JAK3 decreased TEER and AJ localizations of
β-catenin induced increasing of severity in DSS-induced colitis. JAK3
activation led to β-catenin phosphorylation at Tyr-654, which promoted
β-catenin interaction with E-cadherin, thereby facilitated AJ formation
and enhanced the IEC barrier functions. The expression of
differentiation markers of human intestinal epithelial cells (IEC)
depended on the nuclear translocation of phosphorylated form of
JAK3(Mishra, Verma, Alpini, Meng & Kumar, 2013). In the region of SHC,
the CH1 and PID domains were responsible for binding to JAK3. In
situation of IL-2 stimulated of epithelial cells, JAK3 was
auto-phosphorylated. However, SHC recruited tyrosine phosphatases SHP2
and PTP1B to JAK3, thereby dephosphorylated JAK3(Mishra & Kumar, 2014).
Additionally, Surfactant protein C, a key component of pulmonary
surfactant, which is a specific marker of type II alveolar epithelial
cells, is convinced has a connection with JAK/STAT. Misfolded proSP-C
caused subsequently type II alveolar cell injury and inflammation(Hamvas
et al., 2004). The SPC-TK/SPC-KO (surfactant protein C-thymidine
kinase/surfactant protein C knockout) mice showed enhancing Janus kinase
(JAK)/STAT activation which is associated with increased inflammation
and delayed repair(Alsulaimani, 2018). Clinical trials about ARDS
patients’ treatment with exogenous recombinant surfactant protein
C(rSP-C)-based surfactant resulted in improvement in blood oxygenation
and suggested a potential benefit(Spragg et al., 2004).
JAK3 plays a critical role in smooth muscle proliferation and
injury-induced neointima formation. Despite JAK3 has a low level of
expression in normal vascular SMCs, the expression and activity of JAK3
are dramatically induced by PDGF-BB in vitro and by balloon injury in
vivo(Wang, Cui, Chuang & Chen, 2017a). Thus, JAK3 is potential a
therapeutic target to preventing neointimal hyperplasia in proliferative
vascular diseases. Moreover, JAK2 is reported regulating angiotensin II
induced smooth muscle proliferation and vascular remodeling(Wang, Cui,
Chuang & Chen, 2017b). In vitro ALI model, LPS-induced upregulation of
the PI3K/AKT and JAK/STAT signaling pathways in human lung fibroblast,
was further inhibited by KLF4 knockdown(Li, Zhang & Yang, 2019). Muscle
dysfunction, associated with JAK/STAT activation, is related to the low
mobility of ARDS(Files, Sanchez & Morris, 2015).
JAK2 and JAK3 are both potent regulators of Na+/K+ ATPase(Bhavsar et
al., 2014; Hosseinzadeh et al., 2015). That reveals JAK/STAT may
participate in the absorption of surplus fluid during ARDS process by
the Na+/K+-ATPase. In energy
depletion model of DCs and Xenopus laevis oocytes which treated with
2,4-dinitro-phenol, JAK3 was phosphorylated (and therefore activated),
and JAK3 downregulated the Na+/K+-ATPase. Pharmacological inhibition of
JAK3 significantly increased
Na+/K+-ATPase(Hosseinzadehet al.,
2015). Recent studies found that JAK3 directly affected the transport
proteins in partial, including various ion channels, a number of
cellular carriers and the Na+/K+pump including the high-affinity Na+ coupled glucose
transporter SGLT1, the excitatory amino acid transporters EAAT1, EAAT2,
EAAT3 and EAAT4, the peptide transporters PepT1 and PepT2, CreaT1 and
the Na+/K+-ATPase(Sopjani, Thaci,
Krasniqi, Selmonaj, Rinnerthaler & Dermaku-Sopjani, 2017). There need
additional experiments to elucidate the mechanisms and prerequisites of
up- or down-regulation of
Na+/K+-ATPase by JAK3 or JAK2.
Moreover, JAKs also phosphate SHP-2 or PI3K, thus play an important part
in other signal transduction pathways such as Ras/Raf/MAPK/ERK pathway
and PI3K-AKT pathway(Saxena et al., 2007; Wit & de Luca, 2016).
Besides, ROS is revealed participated in the activation of JAK-STAT
signaling and in the pathogenesis of ARDS. In fibroblasts and A-431
carcinoma cells, treatment of H2O2 can
activated STAT1, STAT3 and STAT kinases JAK2 and TYK2 within 5min. And
PDGF uses ROS as a second messenger to regulate STAT activation(Simon,
Rai, Fanburg & Cochran, 1998).