Fibrinolytic Regulation of Pulmonary Epithelial Sodium Channels: a Critical Review

Luminal fluid homeostasis in the respiratory system is crucial to maintain the gas- blood exchange in normal lungs and mucociliary clearance in the airways. Epithelial sodium channels (ENaC) govern ~70% of alveolar fluid clearance. Four ENaC subunits have been cloned, namely, ?, ?, ?, and ? ENaC subunits in mammalian cells. This critical review focuses on the expression and function of ENaC in human and murine lungs, and the post-translational regulation by fibrinolysins. Nebulized urokinase was intratracheally delivered for clinical models of lung injury with unknown mechanisms. The central hypothesis is that proteolytically cleaved ENaC channels composed of four subunits are essential pathways to maintain fluid homeostasis in the airspaces, and that fibrinolysins are potential pharmaceutical ENaC activators to resolve edema fluid. This hypothesis is strongly supported by our following observations: 1) ? ENaC is expressed in the apical membrane of human lung epithelial cells; 2) ? ENaC physically interacts with the other three ENaC counterparts; 3) the features of ??? ENaC channels are conferred by ? ENaC; 4) urokinase activates ENaC activity; 5) urokinase deficiency is associated with a markedly distressed pulmonary ENaC function in vivo; 6) ? ENaC is proteolytically cleaved by urokinase; 7) urokinase augments the density of opening channels at the cell surface; and 8) urokinase extends opening time of ENaC channels to the most extent. Our integrated publications laid the groundwork for an innovative concept of pulmonary transepithelial fluid clearance in both normal and diseased lungs

Upregulation of the WNK4 signaling pathway inhibits epithelial sodium channels of mouse tracheal epithelial cells after influenza A infection

Influenza virus has a significant impact on the respiratory system. The mechanism of how influenza virus impairs the fluid transport in airway is not fully understood. We examined its effects on epithelial sodium channels (ENaC), which are very important for water and salt transport in the respiratory system. We focused on the impacts of influenza virus on ENaC activity in mouse tracheal epithelial cells (MTECs) and applied Ussing chamber apparatus for recording the short-circuit currents in primary cultured MTECs. Expressions of α and γ-ENaC were measured at the protein and mRNA levels by western blot and quantitative real-time polymerase chain reaction, respectively. Roles of the with-no-lysine-kinase-4 (WNK4) pathway were considered in participating influenza virus-involved ENaC regulation by using siRNA to knockdown WNK4 and the physical properties of airway surface liquid (ASL) were detected by confocal microscopy. Our results showed that influenza virus reduced ENaC activity, and the expressions of α and γ-ENaC were decreased at the protein and mRNA levels, respectively. WNK4 expression increased time-dependently at the protein level after influenza virus infection, while knockdown of WNK4 rescued the impact of influenza virus on ENaC and ASL height increased obviously after MTECs were treated with influenza virus. Taken together, these results suggest that influenza virus causes the changes of biophysical profile in the airway by altering the ENaC activity at least partly via facilitating the expression of WNK4

Cpt-Cgmp Is A New Ligand Of Epithelial Sodium Channels

Epithelial sodium channels (ENaC) are localized at the apical membrane of the epithelium, and are responsible for salt and fluid reabsorption. Renal ENaC takes up salt, thereby controlling salt content in serum. Loss-of-function ENaC mutations lead to low blood pressure due to salt-wasting, while gain-of-function mutations cause impaired sodium excretion and subsequent hypertension as well as hypokalemia. ENaC activity is regulated by intracellular and extracellular signals, including hormones, neurotransmitters, protein kinases, and small compounds. Cyclic nucleotides are broadly involved in stimulating protein kinase A and protein kinase G signaling pathways, and, surprisingly, also appear to have a role in regulating ENaC. Increasing evidence suggests that the cGMP analog, CPT-cGMP, activates αβγ-ENaC activity reversibly through an extracellular pathway in a dose-dependent manner. Furthermore, the parachlorophenylthio moiety and ribose 2’-hydroxy group of CPT-cGMP are essential for facilitating the opening of ENaC channels by this compound. Serving as an extracellular ligand, CPT-cGMP eliminates sodium self-inhibition, which is a novel mechanism for stimulating salt reabsorption in parallel to the traditional NO/cGMP/PKG signal pathway. In conclusion, ENaC may be a druggable target for CPT-cGMP, leading to treatments for kidney malfunctions in salt reabsorption

Prkg2 regulates alveolar type 2-mediated re-alveolarization

Background: The cGMP-dependent type 2 protein kinase, encoded by the prkg2 gene, is highly expressed in alveolar type 2 epithelial (AT2) cells. It is unclear whether prkg2 regulates AT2 cell homeostasis and re-alveolarization of injured lungs. This study aimed to investigate the role of prkg2 in the regulation of the fate of AT2 in vitro. Methods: Primary AT2 cells of wild-type (wt) and prkg2--/--mice were co-cultured with fbroblasts as three-dimensional organoids. The colony formation was analyzed between days 4 and 12 post-seeding. EdU assay was used to detect cells with active DNA synthesis. AT1 and AT2 cells in organoids were visualized with anti-podoplanin and antisurfactant protein C antibodies, respectively. Results: Prkg2--/-- AT2 cells developed a greater number of organoids than wt controls. However, compared to wt organoids, a lower number of AT2 but a greater number of AT1 cells were visualized. In addition, a lower number of proliferated cells (EdU+) were observed in prkg2--/-- organoids compared to wt controls. The numbers of organoids and EdU+ cells were signifcantly reduced in protein kinase A (PKA) inhibitor H89-treated wt and prkg2--/-- cultures. Organoids and EdU+ cells were increased by lipopolysaccharides (LPS) in both wt and prkg2--/-- groups. The increase in the proportion of AT1 and AT2 cells in organoids was only seen in wt controls. Conclusions: Prkg2 may regulate the lineage of AT2 cells, which is afected by endotoxins and the interactive PKA signaling pathway

Frequency stability in modern power network from complex network viewpoint

Acknowledgement The work is supported in part by Key Program of Nature Science Fund of Shaanxi Province (2016ZDJC-01), IRT of Shaanxi Province (2013KCT-04).Peer reviewedPostprin

The Reionization History in the Lognormal Model

We study the evolution of baryonic gas before the reionization in the lognormal (LN) model of cosmic clustering. We show that the thermal history of the universe around the reionization can roughly be divided into three epochs: 1) cold dark age $z>z_r$, in which baryon gas is neutral, and opaque to Ly$\alpha$ photons; 2) hot dark age $z_r > z> z_{gp}$, in which a predominant part of baryon gas is ionized and hot, but it is still opaque to Ly$\alpha$ photons; 3) bright age $z<z_{gp}$, in which the universe is ionized highly enough to be transparent to Ly$\alpha$ photons. In the flat cold dark matter cosmological models given by WMAP and COBE, the difference of the two redshifts $z_r - z_{gp}$ is found to be as large as $\sim 10$ with $z_r\sim 17$ and $z_{gp}\sim 7$. This reionization history naturally yields a high optical depth to the CMB $\tau_e \simeq 0.12 - 0.19$ observed by the TE polarization of the WMAP, and a low redshift $z_{gp}$ of the appearance of the Ly$\alpha$ Gunn-Peterson trough $z_{gp} \simeq 6 - 8$ in QSO's absorption spectra. The reason why the universe stays long in an ionized, yet Ly$\alpha$ opaque, stage is because the first photo-ionization heats the intergalactic gas effectively and has balanced the gravitational clustering a long period of time. Therefore, the result of a high $\tau_e$ and low $z_{gp}$ is a common feature of all the models considered. Besides the cosmological parameters, the only free parameter we used in the calculation is $N_{ion}$, the mean ionization photons produced by each baryon in collapsed objects. We take it to be 40 - 80 in the calculation.Comment: AAS Latex file, 29 pages, 6 figures included, accepted for publication in Ap

Estimation of monthly pan evaporation using support vector machine in Three Gorges Reservoir Area, China

Pan evaporation plays a critical role in estimating water budget and modeling crop water requirements. However, it has been measured at a very limited number of meteorological stations. Estimation of pan evaporation from measured meteorological variables offers an important alternative and drawn increasing attention in the recent years. This paper investigated the performance of support vector machine (SVM) in the estimation of monthly pan evaporation using commonly measured meteorological variables in Three Gorges Reservoir Area in China. Evaluation suggested that SVM models showed remarkable performances and significantly outperformed the empirical model. The SVM model with polynomial as kernel function outperformed that with radial basis function. In the case of unavailable measurements of pan evaporation and meteorological variables to construct the SVM model, pan evaporation can be well-estimated by SVM model developed using data at other sites. The results indicated that the SVM method would be a promising alternative over the traditional approaches for estimating pan evaporation from measured meteorological variables