Abstract:Adiponectin (APN), an adipocyte-derived adipokine, has been shown to limit lung injury originating from endothelial cell (EC) damage. Previously we reported that obese mice with low circulatory APN levels exhibited pulmonary vascular endothelial dysfunction. This study was designed to investigate the cellular and molecular mechanisms underlying the pulmonary endothelium-dependent protective effects of APN. Our results demonstrated that in APN 2/2 mice, there was an inherent state of endothelium mitochondrial d… Show more
“…Beside the alveolar epithelium, the pulmonary endothelium is also a critical part of the pulmonary barrier. 65 Succinate has been shown to affect endothelial VEGF and ROS production, 56,66 and therefore, increased alveolar-epithelial succinate could have a secondary effect on the endothelium. Taken together, these studies indicate a protective role of alveolar-epithelial succinate and suggest pharmacologic approaches to elevate alveolar-epithelial succinate levels in ARDS treatment.…”
Acute lung injury (ALI) is an inflammatory lung disease, which manifests itself in patients as acute respiratory distress syndrome (ARDS). Previous studies have implicated alveolar-epithelial succinate in ALI protection. Therefore, we hypothesized that targeting alveolar succinate dehydrogenase SDH A would result in elevated succinate levels and concomitant lung protection. Wild-type (WT) mice or transgenic mice with targeted alveolar-epithelial Sdha or hypoxia-inducible transcription factor Hif1a deletion were exposed to ALI induced by mechanical ventilation. Succinate metabolism was assessed in alveolar-epithelial via mass spectrometry as well as redox measurements and evaluation of lung injury. In WT mice, ALI induced by mechanical ventilation decreased SDHA activity and increased succinate in alveolar-epithelial. In vitro, cell-permeable succinate decreased epithelial inflammation during stretch injury. Mice with inducible alveolar-epithelial Sdha deletion (Sdha loxp/loxp SPC-CreER mice) revealed reduced lung inflammation, improved alveolar barrier function, and attenuated histologic injury. Consistent with a functional role of succinate to stabilize HIF, Sdha loxp/loxp SPC-CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1a loxp/loxp SPC-CreER showed increased inflammation with ALI induced by mechanical ventilation. Finally, wild-type mice treated with intratracheal dimethlysuccinate were protected during ALI. These data suggest that targeting alveolar-epithelial SDHA dampens ALI via succinate-mediated stabilization 2 of 18 | VOHWINKEL Et aL.
“…Beside the alveolar epithelium, the pulmonary endothelium is also a critical part of the pulmonary barrier. 65 Succinate has been shown to affect endothelial VEGF and ROS production, 56,66 and therefore, increased alveolar-epithelial succinate could have a secondary effect on the endothelium. Taken together, these studies indicate a protective role of alveolar-epithelial succinate and suggest pharmacologic approaches to elevate alveolar-epithelial succinate levels in ARDS treatment.…”
Acute lung injury (ALI) is an inflammatory lung disease, which manifests itself in patients as acute respiratory distress syndrome (ARDS). Previous studies have implicated alveolar-epithelial succinate in ALI protection. Therefore, we hypothesized that targeting alveolar succinate dehydrogenase SDH A would result in elevated succinate levels and concomitant lung protection. Wild-type (WT) mice or transgenic mice with targeted alveolar-epithelial Sdha or hypoxia-inducible transcription factor Hif1a deletion were exposed to ALI induced by mechanical ventilation. Succinate metabolism was assessed in alveolar-epithelial via mass spectrometry as well as redox measurements and evaluation of lung injury. In WT mice, ALI induced by mechanical ventilation decreased SDHA activity and increased succinate in alveolar-epithelial. In vitro, cell-permeable succinate decreased epithelial inflammation during stretch injury. Mice with inducible alveolar-epithelial Sdha deletion (Sdha loxp/loxp SPC-CreER mice) revealed reduced lung inflammation, improved alveolar barrier function, and attenuated histologic injury. Consistent with a functional role of succinate to stabilize HIF, Sdha loxp/loxp SPC-CreER experienced enhanced Hif1a levels during hypoxia or ALI. Conversely, Hif1a loxp/loxp SPC-CreER showed increased inflammation with ALI induced by mechanical ventilation. Finally, wild-type mice treated with intratracheal dimethlysuccinate were protected during ALI. These data suggest that targeting alveolar-epithelial SDHA dampens ALI via succinate-mediated stabilization 2 of 18 | VOHWINKEL Et aL.
“…We also did not study the effect of rAPN on lung endothelial cells. Recent evidence implicates APN as key in protecting the lung endothelium from LPS-induced lung injury in adult animals (Shah, Torres, & Bhandari, 2019). Since interstitial edema is often seen early in premature infants that progress to BPD, determining how APN interacts with lung endothelium in health and disease during development would be of interest.…”
Preterm infants are at high risk for developing bronchopulmonary dysplasia and pulmonary hypertension from inflammatory lung injury. In adult models, adiponectin (APN)—an adipocyte‐derived hormone—protects the lung from inflammatory injury and pulmonary vascular remodeling. Cord blood APN levels in premature infants born < 26 weeks gestation are 5% of the level in infants born at term. We previously reported the expression profile of APN and its receptors in neonatal rat lung homogenates during the first 3 weeks of postnatal development. Here, we characterize the expression profile of APN and its receptors in specific lung cells and the effects of exogenous recombinant APN (rAPN) on lipopolysaccharide‐(LPS)‐induced cytokine and chemokine production in total lung homogenates and specific lung cells. In vitro, rAPN added to primary cultures of pulmonary artery smooth muscle cells attenuated the expression of LPS‐induced pro‐inflammatory cytokines while increasing the expression of anti‐inflammatory cytokines. In vivo, intraperitoneal rAPN (2 mg/kg), given 4 hr prior to intrapharyngeal administration of LPS (5 mg/kg) to newborn rats at postnatal day 4, significantly reduced gene and protein expression of the pro‐inflammatory cytokine IL‐1ß and reduced protein expression of the chemokines monocyte chemoattractant protein (MCP‐1) and macrophage inflammatory protein‐1 alpha (MIP‐1α) in the lung. LPS‐induced histopathological changes in the lung were also decreased. Moreover, rAPN given 20 hr after intrapharyngeal LPS had a similar effect on lung inflammation. These findings suggest a role for APN in protecting the lung from inflammation during early stages of lung development.
“…Adiponectin-induced upregulated expression of VEGF is mediated via the activation of AdipoR1, and MMP-2 and MMP-9 are mediated via the activation of both AdipoR1 and AdipoR2 [ 78 ]. Adiponectin appears to play an important role in mitochondrial biogenesis in vascular ECs as evident by a study where Adipo KO mice downregulated the expression of regulatory proteins of mitochondrial biogenesis including PGC-1α, nuclear respiratory factor 1, transcription factor A, Sirt3 and Sirt1 in pulmonary vascular ECs [ 79 ]. Fig.…”
Section: Pleiotropic Role Of Adiponectinmentioning
According to the World Health Organization, metabolic syndrome (MetS) can be defined as a pathological condition characterized by abdominal obesity, insulin resistance, hypertension, and hyperlipidemia. The incidence of MetS keeps rising, as at least 35% of the USA population suffers from MetS. One of the worst comorbidities of metabolic syndrome are cardiovascular diseases that significantly amplifies the mortality associated with this syndrome. There is an urgent need to understand the pathophysiology of MetS to find novel diagnosis, treatment and management to mitigate the MetS and associated complications. Altered circulatory adiponectin levels have been implicated in MetS. Adiponectin has numerous biologic functions including antioxidative, anti-nitrative, anti-inflammatory, and cardioprotective effects. Being a pleiotropic hormone of multiple tissues, tissue-specific key signaling pathways of adiponectin will help finding specific target/s to blunt the pathophysiology of metabolic syndrome and associated disorders. The purpose of this review is to elucidate tissue-specific signaling pathways of adiponectin and possibly identify potential therapeutic targets for MetS as well as to evaluate the potential of adiponectin as a biomarker/therapeutic option in MetS.
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