The activity of AMPK supports the normal function of the endothelial barrier (Xing, Wang, Coughlan, Viollet, Moriasi, & Zou, 2013), while on the other hand, the exposure of LPS ensures that there is inhibition of AMPK, thus accentuating lung injury and endothelial barrier dysfunction (Kratzer et al., 2012). It is a fact that LPS increases the permeability of the endothelium, which occurs once there is a decrease in the AMPK activity. This is consistent with the fact that the activation of AMPK activator, AICAR, emphasizes LP, once it is applied in vitro to test the hyper endothelial permeability.
Experiments done previously have shown that the intratracheal administration of a certain quantity of LPS, 1 mg/ kg, “reduced AMPK phosphorylation at Thr172 in lung tissue extracts” ( (Xing J. , et al., 2013, p.1023). Apart from this, the administration ensures that there is an increase in cell count and the content of protein in the lavage fluid of the bronchial alveolar. Furthermore, there is an increase in the infiltration of the Evans Blue dye into the lungs (Radu & Chernoff, 2013). The presence of AICAR, therefore, ensures that there is attenuation of LPS-induced endothelial hyperpermeability, once the “Rac/ Cdc42/ PAK pathway” is activated and a decrease of the phosphorylation of VE-cadherin takes place (Xing et al., 2013).
Prior treatment of the endothelium with AMPK agonist metformin would automatically suppress the development of ALI, which is induced by LPS, therefore increasing the activity of SOD and MDA (Bułdak et al., 2016). This means that once there is an activation of AMPK by Metformin, there is the inhibition of the stress brought by the oxidation of SOD1 and PGC1a, which leads to a potential value of clinically treating such conditions.
The lack of ability of the neutrophils to do away with any microorganisms is associated with the presence of severe infections, which may lead to an increase in the mortality rates that are associated with sepsis (Liu et al., 2015). At this point, it is important to analyze whether metformin and AMPK affect the bacterial killings, phagocytosis, and the motility of the neutrophils (Park et al., 2013). Following this, results done on various experiments show that activating AMPK enhances the chemotaxis of neutrophils both in the vivo and in in vitro while at the same time restraining the “inhibition of chemotaxis induced by exposure of neutrophils to Lipopolysaccharides (LPS)” (Park et al., 2013, p. 394).
A case of treating neutrophils with metformin increases the cases of bacterial killings and phagocytosis. It is, therefore, true that metformin induces high range polymerization and the creation of neutrophils, which is in contrast to LPS. Therefore, metformin reduces the effects of LPS, which in this case ensures that there is the reduction of the phosphorylation of AMPK (Tsoyi et al., 2011). It means therefore that the activation of AMPK, using agents like metformin, aids in eradicating the bacteria associated with the inhibition of chemotaxis and neutrophil activation.
An imbalance between antioxidation and oxidation is proof that there is involvement in the pathogenesis of acute lung injury (Bargaglia, Olivieria, Bennetta, Prasseb, Muller-Quernheimb, & Rottolia, 2009). Therefore, an activation of the AMPK leads to the inhibition of the acute lung injury, ALI. It is however not proven whether this activation aids in the restoration of the antioxidation and oxidation balance. Experiments done on mice prove that inducing LPS causes pathological changes in acute lung injury. The main effect once the development of the LPS-induced ALI is suppressed by the activation of AMPK is the induction of SODI, which causes the up-regulation of PGC-1 (Kim et al., 2014). The activation of AMPK also has the potential capability of healing LPS- induced ALI (Salminen, Hyttinen, & Kaarniranta, 2011).
Science has proven that LPS plays a major role in augmenting inflammation in ventilated lungs, through the aid of the Gram- positive bacteria, PAM3. This bacterium increases resistance during mechanical ventilation, as compared to LPS. Therefore, it is a fact that LPS enhances inflammation that is ventilator- induced, but does not increase the “pulmonary resistance in ventilated lungs” (Hauber, Karp, Goldmann, Vollmer, & Zabel2, 2010, n.p). When it comes to AMPK, combining it with voluntary exercise training ensures that the performance of the body is increased due to the increased ventilation patterns. As aforementioned, therefore, both AMPK and LPS have an effect on the ventilation patterns but do not influence one another when it comes to this process. As for metformin, if a diabetic person fails to take the drugs as required, then the level of B12 in the blood will reduce therefore causing anemia. This in return would cause deep breathing, in an effort to compensate for the oxygen levels, hence increasing the ventilation process.
References
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