Hypoxia-Inducible Factor Signaling in Inflammatory Lung Injury and Repair.

Inflammatory lung injury is characterized by lung endothelial cell (LEC) death, alveolar epithelial cell (AEC) death, LEC-LEC junction weakening, and leukocyte infiltration, which together disrupt nutrient and oxygen transport. Subsequently, lung vascular repair is characterized by LEC and AEC regeneration and LEC-LEC junction re-annealing, which restores nutrient and oxygen delivery to the injured tissue. Pulmonary hypoxia is a characteristic feature of several inflammatory lung conditions, including acute lung injury (ALI), acute respiratory distress syndrome (ARDS), and severe coronavirus disease 2019 (COVID-19). The vascular response to hypoxia is controlled primarily by the hypoxia-inducible transcription factors (HIFs) 1 and 2. These transcription factors control the expression of a wide variety of target genes, which in turn mediate key pathophysiological processes including cell survival, differentiation, migration, and proliferation. HIF signaling in pulmonary cell types such as LECs and AECs, as well as infiltrating leukocytes, tightly regulates inflammatory lung injury and repair, in a manner that is dependent upon HIF isoform, cell type, and injury stimulus. The aim of this review is to describe the HIF-dependent regulation of inflammatory lung injury and vascular repair. The review will also discuss potential areas for future study and highlight putative targets for inflammatory lung conditions such as ALI/ARDS and severe COVID-19. In the development of HIF-targeted therapies to reduce inflammatory lung injury and/or enhance pulmonary vascular repair, it will be vital to consider HIF isoform- and cell-specificity, off-target side-effects, and the timing and delivery strategy of the therapeutic intervention.

Metabolic Reprogramming in COVID-19.

Plenty of research has revealed virus induced alternations in metabolic pathways, which is known as metabolic reprogramming. Studies focusing on COVID-19 have uncovered significant changes in metabolism, resulting in the perspective that COVID-19 is a metabolic disease. Reprogramming of amino acid, glucose, cholesterol and fatty acid is distinctive characteristic of COVID-19 infection. These metabolic changes in COVID-19 have a critical role not only in producing energy and virus constituent elements, but also in regulating immune response, offering new insights into COVID-19 pathophysiology. Remarkably, metabolic reprogramming provides great opportunities for developing novel biomarkers and therapeutic agents for COVID-19 infection. Such novel agents are expected to be effective adjuvant therapies. In this review, we integrate present studies about major metabolic reprogramming in COVID-19, as well as the possibility of targeting reprogrammed metabolism to combat virus infection.

Hypoxia and viral infectious diseases.

Oxygen-sensing mechanisms allow cells to adapt and respond to changes in cellular oxygen tension, including hypoxic conditions. Hypoxia-inducible factor (HIF) is a central mediator in this fundamental adaptive response, and has critical functions in normal and disease physiology. Viruses have been shown to manipulate HIFs during their life cycle to facilitate replication and invasion. Conversely, HIFs are also implicated in the development of the host immune system and response to viral infections. Here, we highlight the recent revelations of host-pathogen interactions that involve the hypoxic response pathway and the role of HIF in emerging viral infectious diseases, as well as discussing potential antiviral therapeutic strategies targeting the HIF signaling axis.

Silent hypoxia in COVID-19: pathomechanism and possible management strategy.

The novel coronavirus disease 2019 (COVID-19) has become a severe health issue, especially to the patients who develop silent hypoxia condition after SARS-CoV-2 infection. Due to the lack of dyspnoea and extremely low oxygen saturation level, these patients are at exceptionally higher risk. Although the prevalence of silent hypoxia in COVID-19 patients has been evident in several cases, the underlying pathomechanism behind this condition is still unclear. Silent hypoxia in SARS-CoV-2 infected patients can be diagnosed with the help of a pulse oximeter, blood gas levels, and a 6-min walking test. While the clinicians and researchers figure out the exact reason for this phenomenon, the patients must be under strict day-to-day monitoring. In this article, we aim to provide comprehensive insights into the underlying symptoms, mechanism, and possible factors behind the occurrence of silent hypoxia among COVID-19 patients.

Therapeutic Nuclear Magnetic Resonance affects the core clock mechanism and associated Hypoxia-inducible factor-1.

The influence of low intensity electromagnetic fields on circadian clocks of cells and tissues has gained increasing scientific interest, either as a therapeutic tool or as a potential environmental hazard. Nuclear Magnetic Resonance (NMR) refers to the property of certain atomic nuclei to absorb the energy of radio waves under a corresponding magnetic field. NMR forms the basis for Magnetic Resonance Imaging, Magnetic Resonance Spectroscopy and, in a low-intensity form, for NMR therapy (tNMR). Since the circadian clock is bi-directionally intertwined with hypoxic signaling in vertebrates and mammals, we hypothesized that low intensity electromagnetic fields, such as tNMR, might not only affect circadian clocks but also Hypoxia-Inducible Factor-1α (HIF-1α). As master regulator of the hypoxic signaling pathway, HIF-1α is known to dampen the circadian amplitude under reduced oxygen availability, while the hypoxic response of cells and organisms, itself, is tightly clock controlled. In a first experiment, we investigated if tNMR is able to act as Zeitgeber for the core clock mechanism of unsynchronized zebrafish and mouse fibroblast cells, using direct light irradiation and treatment with the glucocorticoid Dexamethasone as references. tNMR significantly affected the cell autonomous clocks of unsynchronized mouse fibroblast cells NIH3-T3, but did not act as a Zeitgeber. Similar to light irradiation and in contrast to treatment with Dexamethasone, tNMR did not synchronize expression profiles of murine clock genes. However, irradiation with tNMR as well as light significantly altered mRNA and protein expression levels of Cryptochrome1, Cryptochrome2 and Clock1 for more than 24 h. Changes in mRNA and protein after different treatment durations, namely 6 and 12 h, appeared to be nonlinear. A nonlinear dose-response relationship is known as hallmark of electromagnetic field induced effects on biological systems. The most prominent alterations were detected in murine HIF-1α protein, again in a nonlinear dose-response. In contrast to murine cells, zebrafish fibroblasts did not respond to tNMR at all. Light, a potent Zeitgeber for the peripheral clocks of fish, led to the expected synchronized clock gene oscillations of high amplitude, as did Dexamethasone. Hence, we conclude, mammalian peripheral clocks are more susceptible to tNMR than the direct light entrainable fish fibroblasts. Although light and tNMR did not act as Zeitgebers for the circadian clocks of unsynchronized murine cells, the significant observed effects might indicate downstream cell-physiological ramifications, which are worth future investigation. However, beside the effects tNMR exerts on the core clock mechanism of mammalian cells, the technology might be the first non-pharmacological approach to modify HIF-1α protein in cells and tissues. HIF-1α and the associated circadian clock play key roles in diseases with underlying ischemic background, such as infarct, stroke, and cancer and, also infectious diseases, such as Covid-19. Hence, low intensity magnetic fields such as tNMR might be of significant medical interest.

HIF-1, the Warburg Effect, and Macrophage/Microglia Polarization Potential Role in COVID-19 Pathogenesis.

Despite the international scientific community's commitment to improve clinical knowledge about coronavirus disease 2019 (COVID-19), knowledge regarding molecular details remains limited. In this review, we discuss hypoxia's potential role in the pathogenesis of the maladaptive immune reaction against severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). The state of infection, with serious respiratory dysfunction, causes tissues to become hypoxic due to a discrepancy between cellular O2 uptake and consumption similar to that seen within tumor tissue during the progression of numerous solid cancers. In this context, the heterogeneous clinical behavior and the multiorgan deterioration of COVID-19 are discussed as a function of the upregulated expression of the hypoxia-inducible factor-1 (HIF-1) and of the metabolic reprogramming associated with HIF-1 and with a proinflammatory innate immune response activation, independent of the increase in the viral load of SARS-CoV-2. Possible pharmacological strategies targeting O2 aimed to improve prognosis are suggested.

Hypoxic preconditioning - A nonpharmacological approach in COVID-19 prevention.

Hypoxia is defined by low oxygen concentration in organs, tissues, and cells. Maintaining oxygen homeostasis represents the essential cellular metabolic process for the structural integrity of tissues in different pathological conditions, including severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Considering the role of hypoxia-inducible factor-1 as the regulator of cellular response to hypoxia and its involvement in angiogenesis, erythropoiesis, glucose metabolism, inflammation, we propose hypoxic preconditioning (HPC) as a novel prevention therapeutic approach on healthy contacts of patients with coronavirus disease-2019 (COVID-19). To date, several studies revealed the beneficial effects of HPC in ischemia, kidney failure, and in pulmonary function recovery of patients who underwent lung surgery. HPC increases the expression of factors that promote cell survival and angiogenesis, induces an anti-inflammatory outcome, triggers coordinated hypoxia responses that promote erythropoiesis, and mobilizes the circulating progenitor cells. Furthermore, the mesenchymal stem cells (MSC) exposed to HPC show improvement of their regenerative capacities and increases the effectiveness of stem cell therapy in different pathologies, including COVID-19. In conclusion, HPC should be considered as an approach with beneficial outcomes and without significant side effects when the organism is severely exposed to the same stressor. HPC appears as a trigger to mechanisms that improve and maintain tissue oxygenation and repair, a main goal in different pathologies, including COVID-19 or other respiratory conditions.

Adenosine at the Interphase of Hypoxia and Inflammation in Lung Injury.

Hypoxia and inflammation often coincide in pathogenic conditions such as acute respiratory distress syndrome (ARDS) and chronic lung diseases, which are significant contributors to morbidity and mortality for the general population. For example, the recent global outbreak of Coronavirus disease 2019 (COVID-19) has placed viral infection-induced ARDS under the spotlight. Moreover, chronic lung disease ranks the third leading cause of death in the United States. Hypoxia signaling plays a diverse role in both acute and chronic lung inflammation, which could partially be explained by the divergent function of downstream target pathways such as adenosine signaling. Particularly, hypoxia signaling activates adenosine signaling to inhibit the inflammatory response in ARDS, while in chronic lung diseases, it promotes inflammation and tissue injury. In this review, we discuss the role of adenosine at the interphase of hypoxia and inflammation in ARDS and chronic lung diseases, as well as the current strategy for therapeutic targeting of the adenosine signaling pathway.

Dysregulation in Akt/mTOR/HIF-1 signaling identified by proteo-transcriptomics of SARS-CoV-2 infected cells.

How severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infections engage cellular host pathways and innate immunity in infected cells remains largely elusive. We performed an integrative proteo-transcriptomics analysis in SARS-CoV-2 infected Huh7 cells to map the cellular response to the invading virus over time. We identified four pathways, ErbB, HIF-1, mTOR and TNF signaling, among others that were markedly modulated during the course of the SARS-CoV-2 infection in vitro. Western blot validation of the downstream effector molecules of these pathways revealed a dose-dependent activation of Akt, mTOR, S6K1 and 4E-BP1 at 24 hours post infection (hpi). However, we found a significant inhibition of HIF-1α through 24hpi and 48hpi of the infection, suggesting a crosstalk between the SARS-CoV-2 and the Akt/mTOR/HIF-1 signaling pathways. Inhibition of the mTOR signaling pathway using Akt inhibitor MK-2206 showed a significant reduction in virus production. Further investigations are required to better understand the molecular sequelae in order to guide potential therapy in the management of severe coronavirus disease 2019 (COVID-19) patients.