4-Hydroxyphenylacetic Acid Attenuated Inflammation and Edema via Suppressing HIF-1α in Seawater Aspiration-Induced Lung Injury in Rats

Abstract

4-Hydroxyphenylacetic acid (4-HPA) is an active component of Chinese herb Aster tataricus which had been widely used in China for the treatment of pulmonary diseases. The aim of this study is to investigate the effect of 4-HPA on seawater aspiration-induced lung injury. Pulmonary inflammation and edema were assessed by enzyme-linked immunosorbent assay (ELISA), bronchoalveolar lavage fluid (BALF) white cell count, Evans blue dye analysis, wet to dry weight ratios, and histology study. Hypoxia-inducible factor-1α (HIF-1α) siRNA and permeability assay were used to study the effect of 4-HPA on the production of inflammatory cytokines and monolayer permeability in vitro. The results showed that 4-HPA reduced seawater instillation-induced mortality in rats. In lung tissues, 4-HPA attenuated hypoxia, inflammation, vascular leak, and edema, and decreased HIF-1α protein level. In primary rat alveolar epithelial cells (AEC), 4-HPA decreased hypertonicity- and hypoxia-induced HIF-1α protein levels through inhibiting the activations of protein translational regulators and via promoting HIF-1α protein degradation. In addition, 4-HPA lowered inflammatory cytokines levels through suppressing hypertonicity- and hypoxia-induced HIF-1α in NR8383 macrophages. Moreover, 4-HPA decreased monolayer permeability through suppressing hypertonicity and hypoxia-induced HIF-1α, which was mediated by inhibiting vascular endothelial growth factor (VEGF) in rat lung microvascular endothelial cell line (RLMVEC). In conclusion, 4-HPA attenuated inflammation and edema through suppressing hypertonic and hypoxic induction of HIF-1α in seawater aspiration-induced lung injury in rats.

Erythropoietin Pretreatment Attenuates Seawater Aspiration-Induced Acute Lung Injury in Rats

“…The hyperosmolar seawater has direct effect on the lung epithelial cells and causes the infiltration of inflammation cells into the alveolar spaces and releases various molecules, leading to lung edema and deterioration of gas exchange [3][4][5][6]15]. Proinflammatory cytokines, such as TNF-α and IL-6, are critical for initiating, amplifying, and perpetuating organ injury [5,6].…”

“…Drowning is the second accidental cause of death in the world, especially for children and young adults [1][2][3].…”

“…Seawater aspiration represents one of the most important causes of acute lung injury (ALI), which is characterized by pulmonary edema and severe refractory hypoxemia [1][2][3][4]. In addition, the increased alveolar-capillary permeability caused by seawater aspiration allows the inflammatory cells infiltrate into the alveolar spaces and releases several molecules, such as pro-inflammatory cytokines and reactive oxygen species, leading to further pulmonary edema and deterioration of gas exchange [3,5,6]. Thus, agents that inhibit the overwhelming inflammatory responses and oxidative stress process may provide a therapeutic option for the treatment of seawater aspiration-induced ALI.…”

Differential expression of novel metabolic and immunological biomarkers in oysters challenged with a virulent strain of OsHV-1

“…4-hydroxyphenylacetic acid (4-HPA) is a tyrosine-derived metabolite with antioxidant activity that can scavenge reactive oxygen and nitrogen species in vitro and in vivo (Biskup et al 2013), and also has an ability to reduce excessive release of proinflammatory cytokines which protects against inflammation and disease (Liu et al 2014;Ford et al 2016). Increased levels of 4-HPA are associated with various mammalian disease pathologies and inborn errors in metabolism (Kikuchi et al 2010;Nishiumi et al 2010;Hori et al 2011;Manna et al 2015;Xiong et al 2015;Kurko et al 2016).…”

Enhanced Re-Endothelialization of Decellularized Rat Lungs

“…23 For all lungs the first appearance of FITC-Dextran was found in the fourth fraction of the perfusate, while the peak concentration was observed in the fifth fraction (Fig. 9).…”