Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer

Hunyor, Imre; Cook, Kristina M.

doi:10.1152/ajpregu.00036.2018

Cited by 98 publications

(123 citation statements)

References 167 publications

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“…The first one is the pO 2 used in the study. Indeed, in human healthy tissue, the physiological normoxia is comprised mostly between 4% O 2 (muscle) and 9.5% O 2 (kidney, outer cortex) 46,47 . In this study, normoxia and the cyH reoxygenation were performed by exposing cells to atmospheric air (21% O 2 ).…”

Section: Discussionmentioning

confidence: 99%

“…In this study, normoxia and the cyH reoxygenation were performed by exposing cells to atmospheric air (21% O 2 ). Nonetheless, the hypoxia value that we used was physiologically relevant since O 2 saturation in tumor is comprised between 1 and 2% O 2 in a majority of solid tumors 38,47 . Secondly, we showed that cyH induced a pro-inflammatory phenotype in M0 and M1 macrophages in both BMDM and THP-1 macrophages.…”

Section: Discussionmentioning

confidence: 99%

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Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

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Cycling hypoxia (cyH), also called intermittent hypoxia, occurs in solid tumors and affects different cell types in the tumor microenvironment and in particular the tumor-associated macrophages (TAMs). As cyH and TAMs both favor tumor progression, we investigated whether cyH could drive the pro-tumoral phenotype of macrophages. Here, the effects of cyH on human THP-1 macrophages and murine bone marrow-derived macrophages (BMDM), either unpolarized M0, or polarized in M1 or M2 phenotype were studied. In M0 macrophages, cyH induced a pro-inflammatory phenotype characterized by an increase in tnfα and IL-8/MIP-2 secretion. CyH amplified the pro-inflammatory phenotype of M1 macrophages evidenced by an increased pro-inflammatory cytokine secretion and pro-inflammatory gene expression. Furthermore, cyH increased c-jun activation in human M0 macrophages and highly increased c-jun and NF-κB activation in M1 macrophages. C-jun and p65 are implicated in the effects of cyH on M0 and M1 macrophages since inhibition of their activation prevented the cyH pro-inflammatory effects. In conclusion, we demonstrated that cyH induces or amplifies a pro-inflammatory phenotype in M0 and M1 macrophages by activating JNK/p65 signaling pathway. These results highlight a specific role of cyH in the amplification of tumor-related inflammation by modulating the inflammatory phenotype of macrophages. Tumors are complex tissues composed of multiple cell types interacting and influencing each other, namely malignant cells and stromal cells like endothelial cells, immune cells and fibroblasts 1. The intricate combination of tumor microenvironment composition and environmental factors strongly determines tumor outcome 2. A major factor altering the tumor microenvironment is the presence of low oxygen tension called hypoxia, that is a common feature of malignant tumors 3. Two types of hypoxia can be distinguished: chronic and cycling hypoxia (cyH). Chronic hypoxia (chH) is associated to the limited oxygen distribution in a tissue; it is mainly the result of uncontrolled proliferation of O 2-consuming cancer cells and the O 2 diffusion gradient from blood capillaries 4,5. In contrast, cyH, also called intermittent hypoxia, is related to the irregular erythrocyte flux circulating in the anarchical tumor blood network characterized by the presence of temporary occlusions 6-8. The instability of blood flow leads to periods of hypoxia followed by periods of reoxygenation, occurring over hours through a clear pattern of periodicity 9. We previously demonstrated that cyH amplifies the endothelial inflammatory response induced by TNFα notably through an overactivation of NF-κB. Moreover, we showed that cyH enhances the overall tumor inflammation characterized by a global increase in inflammatory gene expression and by an increase in intratumor leukocyte infiltration in tumor-bearing mice 10. Inflammation is indeed described to be mutagenic and to favor proliferation and survival of malignant cells, angiogenesis, metastasis, corruption of the adaptive immu...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Delprat

Tellier

Demazy

et al. 2020

Sci Rep

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“…While some models employ only single cell type spheroids (146), more complex platforms, reflecting physiological interactions found in vivo include multiple cell types in a 3D structure, such as cancer stromal or endothelial cells (147,148) as reviewed earlier (149). For example, a study investigating the role of OSA in cancer employed a 3D cell culture model comprising both tumor spheroids and patient-derived monocytes subjected to IH and found that the monocyte-induced HIF-1α-dependent production of VEGF promoted tumor growth (150), providing some molecular insights into the link between the two diseases (151).…”

Section: D Cell Culturesmentioning

confidence: 99%

Technical Feasibility and Physiological Relevance of Hypoxic Cell Culture Models

Pavlacky

Polàk

2020

Front. Endocrinol.

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Hypoxia is characterized as insufficient oxygen delivery to tissues and cells in the body and is prevalent in many human physiology processes and diseases. Thus, it is an attractive state to experimentally study to understand its inner mechanisms as well as to develop and test therapies against pathological conditions related to hypoxia. Animal models in vivo fail to recapitulate some of the key hallmarks of human physiology, which leads to human cell cultures; however, they are prone to bias, namely when pericellular oxygen concentration (partial pressure) does not respect oxygen dynamics in vivo. A search of the current literature on the topic revealed this was the case for many original studies pertaining to experimental models of hypoxia in vitro. Therefore, in this review, we present evidence mandating for the close control of oxygen levels in cell culture models of hypoxia. First, we discuss the basic physical laws required for understanding the oxygen dynamics in vitro, most notably the limited diffusion through a liquid medium that hampers the oxygenation of cells in conventional cultures. We then summarize up-to-date knowledge of techniques that help standardize the culture environment in a replicable fashion by increasing oxygen delivery to the cells and measuring pericellular levels. We also discuss how these tools may be applied to model both constant and intermittent hypoxia in a physiologically relevant manner, considering known values of partial pressure of tissue normoxia and hypoxia in vivo, compared to conventional cultures incubated at rigid oxygen pressure. Attention is given to the potential influence of three-dimensional tissue cultures and hypercapnia management on these models. Finally, we discuss the implications of these concepts for cell cultures, which try to emulate tissue normoxia, and conclude that the maintenance of precise oxygen levels is important in any cell culture setting.

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“…Hypoxia can result in many severe complications such as the impairment of the lung and heart, as well as certain immune system disorders, including asthma and allergic rhinitis (Davies, Bishopp, Wharton, Turner, & Mansur, 2019; Gadi, Wali, & Koshak, 2017; Kukwa et al., 2018; Ramos, Nader, & Meira, 2019). In instances such as these, hypoxia is often considered to be the primary clinical symptom of OSA, which needs to be solved first (Dewan, Nieto, & Somers, 2015; Hunyor & Cook, 2018). However, OSA related to mild upper airway obstruction can remain untreated if hypoxia can be compromised by mouth breathing, which means that mouth breathing allows the blood oxygen content to stabilize (Chowanetz, Schott, & Jany, 1987).…”

Section: Introductionmentioning

confidence: 99%

Mouth breathing impairs the development of temporomandibular joint at a very early stage

Sun

et al. 2020

Oral Diseases

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Objectives The study aimed to explore the effects of mouth breathing and hypoxia on the condyle of temporomandibular joint (TMJ) via two animal models. Methods 24 four‐week‐old rats were randomly separated into three groups, consisting of eight control rats, eight intermittent hypoxia (IH) rats, and eight intermittent nasal obstruction (INO) rats. We use the IH model and the INO model to simulate children suffering from hypoxia and mouth breathing. After 16 days, the condyle of TMJ and surrounding white adipose tissue (WAT) and skeletal muscle tissue were obtained for further staining and qRT‐PCR. Finally, RNA‐seq was used to verify the results. Results The intermittent hypoxia cannot significantly change the overall structure in the cause of short‐term hypoxia stimulation, but the intermittent nasal obstruction can alter the condyle, WAT, and muscle, while also introducing noticeable structural changes in tissue hypoxia and macrophage infiltration. Sequencing data verified these findings and also suggested that this process might involve the Hif‐1α/Vegf axis. Conclusions Our findings reveal the very early structural impact of mouth breathing on condyle reconstruction in rat models, and hypoxia does not induce evident alteration on condyle. However, since these results are mainly focused on rats, further studies are needed to understand its effects on humans.

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Models of intermittent hypoxia and obstructive sleep apnea: molecular pathways and their contribution to cancer

Cited by 98 publications

References 167 publications

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Cycling hypoxia promotes a pro-inflammatory phenotype in macrophages via JNK/p65 signaling pathway

Technical Feasibility and Physiological Relevance of Hypoxic Cell Culture Models

Mouth breathing impairs the development of temporomandibular joint at a very early stage

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