Acute Hyperglycemia Aggravates Lung Injury via Activation of the SGK1–NKCC1 Pathway

Abstract

Acute lung injury (ALI) is characterized by severe hypoxemia and has significantly high mortality rates. Acute hyperglycemia occurs in patients with conditions such as sepsis or trauma, among others, and it results in aggravated inflammation and induces damage in patients with ALI. Regulation of alveolar fluid is essential for the development and resolution of pulmonary edema in lung injury. Pulmonary sodium-potassium-chloride co-transporter 1 (NKCC1) regulates the net influx of ions and water into alveolar cells. The activation of with-no-lysine kinase 4 (WNK4), STE20/SPS1-related proline/alanine rich kinase (SPAK) and the NKCC1 pathway lead to an increase in the expression of NKCC1 and aggravation of ALI. Moreover, hyperglycemia is known to induce NKCC1 expression via the activation of the serum-glucocorticoid kinase 1 (SGK1)–NKCC1 pathway. We aim to evaluate the influence of acute hyperglycemia on the SGK1–NKCC1 pathway in ALI. ALI was induced using a high tidal volume for four hours in a rat model. Acute hyperglycemia was induced by injection with 0.5 mL of 40% glucose solution followed by continuous infusion at 2 mL/h. The animals were divided into sham, sham+ hyperglycemia, ALI, ALI + hyperglycemia, ALI + inhaled bumetanide (NKCC1 inhibitor) pretreatment, ALI + hyperglycemia + inhalational bumetanide pretreatment, and ALI + hyperglycemia + post-ALI inhalational bumetanide groups. Severe lung injury along with pulmonary edema, alveolar protein leakage, and lung inflammation was observed in ALI with hyperglycemia than in ALI without hyperglycemia. This was concurrent with the higher expression of pro-inflammatory cytokines, infiltration of neutrophils and alveolar macrophages (AM) 1, and NKCC1 expression. Inhalational NKCC1 inhibitor significantly inhibited the SGK1–NKCC1, and WNK4–SPAK–NKCC1 pathways. Additionally, it reduced pulmonary edema, inflammation, levels of pro-inflammatory cytokines, neutrophils and AM1 and increased AM2. Therefore, acute hyperglycemia aggravates lung injury via the further activation of the SGK1–NKCC1 pathway. The NKCC1 inhibitor can effectively attenuate lung injury aggravated by acute hyperglycemia.