Hypoxia-Inducible Factor (HIF)-1α Promotes Inflammation and Injury Following Aspiration-Induced Lung Injury in Mice

Suresh, Madathilparambil V.; Balijepalli, Sanjay; Zhang, Boya; Singh, Vikas Vikram; Swamy, Samantha; Panicker, Sreehari; Dolgachev, Vladislov A.; Subramanian, Chitra; Ramakrishnan, S; Thomas, Bivin; Rao, Tejeshwar C.; Delano, Matthew J.; Machado-Aranda, David; Shah, Yatrik M.; Raghavendran, Krishnan

doi:10.1097/shk.0000000000001312

Cited by 35 publications

(64 citation statements)

References 36 publications

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“…HIF‐1α was not strongly expressed in the injured groups (HCl‐ZEEP), suggesting that tissue hypoxia did not mediate neutrophil activation and migration and that elevated lactate‐to‐pyruvate ratio was primarily the result of inflammation. Our observation is consistent with another study of aspiration pneumonitis in a murine model showing mild HIF‐1α elevation 5 hours after acid instillation 34 . Therefore, it is likely that we did observe an increase in HIF‐1α, as our study ended 4 hours after acid instillation.…”

Section: Discussionsupporting

confidence: 92%

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome

et al. 2020

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Increased pulmonary lactate production is correlated with severity of lung injury and outcome in acute respiratory distress syndrome (ARDS) patients. This study was conducted to investigate the relative contributions of inflammation and hypoxia to the lung's metabolic shift to glycolysis in an experimental animal model of ARDS using hyperpolarized (HP) 13 C MRI. Fifty-three intubated and mechanically ventilated male rats were imaged using HP 13 C MRI before, and 1, 2.5 and 4 hours after saline (sham) or hydrochloric acid (HCl; 0.5 ml/kg) instillation in the trachea, followed by protective and nonprotective mechanical ventilation (HCl-PEEP and HCl-ZEEP) or the start of moderate or severe hypoxia (Hyp90 and Hyp75 groups). Pulmonary and cardiac HP lactate-to-pyruvate ratios were compared among groups for different time points. Postmortem histology and immunofluorescence were used to assess lung injury severity and quantify the expression of innate inflammatory markers and local tissue hypoxia. HP pulmonary lactate-to-pyruvate ratio progressively increased in rats with lung injury and moderate hypoxia (HCl-ZEEP), with no significant change in pulmonary lactate-to-pyruvate ratio in noninjured but moderately hypoxic rats (Hyp90). Pulmonary lactate-to-pyruvate ratio was elevated in otherwise healthy lung tissue only in severe systemic hypoxia (Hyp75 group). ex vivo histological and immunopathological assessment further confirmed the link between elevated glycolysis and the recruitment into and presence of activated neutrophils in injured lungs. HP lactateto-pyruvate ratio is elevated in injured lungs predominantly as a result of increased glycolysis in activated inflammatory cells, but can also increase due to severe inflammation-induced hypoxia.

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Section: Discussionsupporting

confidence: 92%

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome

et al. 2020

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“…HIF-2α upon activation increases the expression of vascular-endothelial protein thyrosine phosphatase, which in turn decreases VEcaderin phosphorylation, supporting the integrity of adherens junctions and preventing loss of endothelial barrier function [64]. Contrarily, expression of HIF-1α in alveolar epithelial cells enhances lung inflammation in a NF-kB mediated way [65] and favors a cell-mediated inflammation (CD4+ CD8+) and proinflammatory cytokines (IL-2 and TNFα), which proportionately downregulate CD55 and augment complement-mediated endothelial damage [8]. Moreover, myeloid cell HIF-1α is a key driver of myeloid cell response in hypoxic and inflammatory microenvironments by modulating cellular energetics, upregulating glycolytic enzymes and glucose transporters to permit ATP generation under conditions of hypoxia, and preventing apoptosis of innate immunity cells.…”

Section: Hypoxia-mediated Endothelial Damagementioning

confidence: 99%

COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure

2020

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COVID-19 pandemia is a major health emergency causing hundreds of deaths worldwide. The high reported morbidity has been related to hypoxia and inflammation leading to endothelial dysfunction and aberrant coagulation in small and large vessels. This review addresses some of the pathways leading to endothelial derangement, such as complement, HIF-1α, and ABL tyrosine kinases. This review also highlights potential targets for prevention and therapy of COVID-19-related organ damage and discusses the role of marketed drugs, such as eculizumab and imatinib, as suitable candidates for clinical trials.

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“…A close link exists between hypoxia and inflammation [ 73 ]. Previous works have reported that different organs in the hypoxic environment exhibit different responses at the transcriptional, translational, and post-translational levels [ 77 , 78 ]. HIF-1α, a pivotal transcription factor in hypoxic induction, activates iNOS gene expression, contributing to increased NO synthesis.…”

Section: Inflammation In Osasmentioning

confidence: 99%

The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome

Liu

Ouyang

et al. 2020

J Neuroinflammation

126

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Obstructive sleep apnea syndrome (OSAS), a state of sleep disorder, is characterized by repetitive apnea, chronic hypoxia, oxygen desaturation, and hypercapnia. Previous studies have revealed that intermittent hypoxia (IH) conditions in OSAS patients elicited neuron injury (especially in the hippocampus and cortex), leading to cognitive dysfunction, a significant and extraordinary complication of OSAS patients. The repeated courses of airway collapse and obstruction in OSAS patients resulted in apnea and arousal during sleep, leading to IH and excessive daytime sleepiness (EDS) and subsequently contributing to the development of inflammation. IH-mediated inflammation could further trigger various types of cognitive dysfunction. Many researchers have found that, besides continuous positive airway pressure (CPAP) treatment and surgery, anti-inflammatory substances might alleviate IH-induced neurocognitive dysfunction. Clarifying the role of inflammation in IH-mediated cognitive impairment is crucial for potentially valuable therapies and future research in the related domain. The objective of this article was to critically review the relationship between inflammation and cognitive deficits in OSAS.

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Hypoxia-Inducible Factor (HIF)-1α Promotes Inflammation and Injury Following Aspiration-Induced Lung Injury in Mice

Cited by 35 publications

References 36 publications

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome

Pulmonary pyruvate metabolism as an index of inflammation and injury in a rat model of acute respiratory distress syndrome

COVID-19-driven endothelial damage: complement, HIF-1, and ABL2 are potential pathways of damage and targets for cure

The relationship between inflammation and neurocognitive dysfunction in obstructive sleep apnea syndrome

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