by Keyword: Intermittent hypoxia

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Torres, M., Martinez-Garcia, M. A., Campos-Rodriguez, F., Gozal, D., Montserrat, J. M., Navajas, D., Farré, R., Almendros, I., (2020). Lung cancer aggressiveness in an intermittent hypoxia murine model of postmenopausal sleep apnea Menopause 27, (6), 706-713

Objective: Intermittent hypoxia (IH)—a hallmark of obstructive sleep apnea (OSA)—enhances lung cancer progression in mice via altered host immune responses that are also age and sex-dependent. However, the interactions of menopause with IH on tumor malignant properties remain unexplored. Here, we aimed to investigate lung cancer outcomes in the context of ovariectomy (OVX)-induced menopause in a murine model of OSA. Methods: Thirty-four female mice (C57BL/6, 12-week-old) were subjected to bilateral OVX or to Sham intervention. Six months after surgery, mice were pre-exposed to either IH or room air (RA) for 2 weeks. Then, 105 lung carcinoma (LLC1) cells were injected subcutaneously in the left flank, with IH or RA exposures continued for 4 weeks. Tumor weight, tumor invasion, and spontaneous lung metastases were assessed. Tumor-associated macrophages (TAMs) were isolated and subjected to flow cytometry polarity evaluation along with assessment of TAMs modulation of LLC1 proliferation in vitro. To determine the effect of IH and OVX on each experimental variable, a two-way analysis of variance was performed. Results: IH and OVX promoted a similar increase in tumor growth (2-fold; P = 0.05 and 1.74-fold; P < 0.05, respectively), and OVX-IH further increased it. Regarding lung metastasis, the concurrence of OVX in mice exposed to IH enhanced the number of metastases (23.7 ± 8.0) in comparison to those without OVX (7.9 ± 2.8; P < 0.05). The pro-tumoral phenotype of TAMS, assessed as M2/M1 ratio, was increased in OVX (0.06 ± 0.01; P < 0.01) and IH (0.06 ± 0.01; P < 0.01) compared with sham/RA conditions (0.14 ± 0.03). The co-culture of TAMS with naive LLC1 cells enhanced their proliferation only under IH. Conclusion: In female mice, both the IH that is characteristically present in OSA and OVX as a menopause model emerge as independent contributors that promote lung cancer aggressiveness and seemingly operate through alterations in the host immune response.

Keywords: Animal models, Cancer progression, Intermittent hypoxia, Menopause, Obstructive sleep apnea, Ovariectomy

Campillo, N., Jorba, I., Schaedel, L., Casals, B., Gozal, D., Farré, R., Almendros, I., Navajas, D., (2016). A novel chip for cyclic stretch and intermittent hypoxia cell exposures mimicking obstructive sleep apnea Frontiers in Physiology 7, Article 319

Intermittent hypoxia (IH), a hallmark of obstructive sleep apnea (OSA), plays a critical role in the pathogenesis of OSA-associated morbidities, especially in the cardiovascular and respiratory systems. Oxidative stress and inflammation induced by IH are suggested as main contributors of end-organ dysfunction in OSA patients and animal models. Since the molecular mechanisms underlying these in vivo pathological responses remain poorly understood, implementation of experimental in vitro cell-based systems capable of inducing high-frequency IH would be highly desirable. Here, we describe the design, fabrication, and validation of a versatile chip for subjecting cultured cells to fast changes in gas partial pressure and to cyclic stretch. The chip is fabricated with polydimethylsiloxane (PDMS) and consists of a cylindrical well-covered by a thin membrane. Cells cultured on top of the membrane can be subjected to fast changes in oxygen concentration (equilibrium time ~6 s). Moreover, cells can be subjected to cyclic stretch at cardiac or respiratory frequencies independently or simultaneously. Rat bone marrow-derived mesenchymal stem cells (MSCs) exposed to IH mimicking OSA and cyclic stretch at cardiac frequencies revealed that hypoxia-inducible factor 1a (HIF-1a) expression was increased in response to both stimuli. Thus, the chip provides a versatile tool for the study of cellular responses to cyclical hypoxia and stretch.

Keywords: Cell stretch, Hypoxia-inducible factor, Intermittent hypoxia, Lab-on-a-chip, Obstructive sleep apnea

Almendros, I., Montserrat, J. M., Torres, M., Dalmases, M., Cabañas, M. L., Campos-Rodríguez, F., Navajas, D., Farré, R., (2013). Intermittent hypoxia increases melanoma metastasis to the lung in a mouse model of sleep apnea Respiratory Physiology & Neurobiology , 186, (3), 303-307

Obstructive sleep apnea (OSA) has recently been associated with an increased risk of cancer incidence and mortality in humans. Experimental data in mice have also shown that intermittent hypoxia similar to that observed in OSA patients enhances tumor growth. The aim of this study was to test the hypothesis that intermittent hypoxia mimicking OSA enhances lung metastasis. A total of 75 C57BL/6J male mice (10-week-old) were subjected to either spontaneous or induced melanoma lung metastasis. Normoxic animals breathed room air and intermittent hypoxic animals were subjected to cycles of 20s of 5% O2 followed by 40s of room air for 6h/day. Spontaneous and induced lung metastases were studied after subcutaneous and intravenous injection of B16F10 melanoma cells, respectively. Compared with normoxia, intermittent hypoxia induced a significant increase in melanoma lung metastasis. These animal model results suggest that intermittent hypoxia could contribute to cancer metastasis in patients with OSA.

Keywords: Intermittent hypoxia, Melanoma, Metastasis, OSA

Almendros, I., Montserrat, J. M., Torres, M., Bonsignore, M. R., Chimenti, L., Navajas, D., Farre, R., (2012). Obesity and intermittent hypoxia increase tumor growth in a mouse model of sleep apnea Sleep Medicine , 13, (10), 1254-1260

Background: Intermittent hypoxia and obesity which are two pathological conditions commonly found in patients with obstructive sleep apnea (OSA), potentially enhance cancer progression. Objective: To investigate whether obesity and/or intermittent hypoxia (IH) mimicking OSA affect tumor growth. Methods: A subcutaneous melanoma was induced in 40 mice [22 obese (40-45 g) and 18 lean (20-25 g)] by injecting 10(6) B16F10 cells in the flank. Nineteen mice (10 obese/9 lean) were subjected to IH (6 h/day for 17 days). A group of 21 mice (12 obese/9 lean) were kept under normoxia. At day 17, tumors were excised, weighed and processed to quantify necrosis and endothelial expression of vascular endothelial growth factor (VEGF) and CD-31. VEGF in plasma was also assessed. Results: In lean animals, IH enhanced tumor growth from 0.81 +/- 0.17 to 1.95 +/- 0.32 g. In obese animals, a similar increase in tumor growth (1.94 +/- 0.18 g) was observed under normoxia, while adding IH had no further effect (1.69 +/- 0.23 g). IH only promoted an increase in tumoral necrosis in lean animals. However, obesity under normoxic conditions increased necrosis, VEGF and CD-31 expression in tumoral tissue. Plasma VEGF strongly correlated with tumor weight (rho = 0.76, p < 0.001) in the whole sample; it increased in lean IH-treated animals from 66.40 +/- 3.47 to 108.37 +/- 9.48 pg/mL, p < 0.001), while the high baseline value in obese mice (106.90 +/- 4.32 pg/mL) was unaffected by IH. Conclusions: Obesity and IH increased tumor growth, but did not appear to exert any synergistic effects. Circulating VEGF appeared as a crucial mediator of tumor growth in both situations.

Keywords: Intermittent hypoxia, Obesity, Cancer, Sleep apnea, Animal model

Almendros, Isaac, Farre, Ramon, Planas, Anna M., Torres, Marta, Bonsignore, Maria R., Navajas, Daniel, Montserrat, Josep M., (2011). Tissue oxygenation in brain, muscle, and fat in a rat model of sleep apnea: Differential effect of obstructive apneas and intermittent hypoxia Sleep , 34, (8), 1127-1133

Study Objectives: To test the hypotheses that the dynamic changes in brain oxygen partial pressure (PtO(2)) in response to obstructive apneas or to intermittent hypoxia differ from those in other organs and that the changes in brain PtO(2) in response to obstructive apneas is a source of oxidative stress. Design: Prospective controlled animal study. Setting: University laboratory. Participants: 98 Sprague-Dawley rats. Interventions: Cerebral cortex, skeletal muscle, or visceral fat tissues were exposed in anesthetized animals subjected to either obstructive apneas or intermittent hypoxia (apneic and hypoxic events of 15 s each and 60 events/h) for 1 h. Measurements and Results: Arterial oxygen saturation (spO(2)) presented a stable pattern, with similar desaturations during both stimuli. The PtO(2) was measured by a microelectrode. During obstructive apneas, a fast increase in cerebral PtO(2) was observed (38.2 +/- 3.4 vs. 54.8 +/- 5.9 mm Hg) but not in the rest of tissues. This particular cerebral response was not found during intermittent hypoxia. The cerebral content of reduced glutathione was decreased after obstructive apneas (46.2% +/- 15.2%) compared to controls (100.0% +/- 14.7%), but not after intermittent hypoxia. This antioxidant consumption after obstructive apneas was accompanied by increased cerebral lipid peroxidation under this condition. No changes were observed for these markers in the other tissues. Conclusions: These results suggest the cerebral cortex could be protected in some way from hypoxic periods caused by obstructive apneas. The increased cerebral PtO(2) during obstructive apneas may, however, cause harmful effects (oxidative stress). The obstructive apnea model appears to be more adequate than the intermittent hypoxia model for studying brain changes associated with OSA.

Keywords: Tissue oxygenation, Obstructive apnea, Intermittent hypoxia, Animal model, Oxidative stress

Almendros, I., Montserrat, J. M., Torres, M., Gonzalez, C., Navajas, D., Farre, R., (2010). Changes in oxygen partial pressure of brain tissue in an animal model of obstructive apnea Respiratory Research , 11, (3), 1-6

Cognitive impairment is one of the main consequences of obstructive sleep apnea (OSA) and is usually attributed in part to the oxidative stress caused by intermittent hypoxia in cerebral tissues. The presence of oxygen-reactive species in the brain tissue should be produced by the deoxygenation-reoxygenation cycles which occur at tissue level during recurrent apneic events. However, how changes in arterial blood oxygen saturation (SpO(2)) during repetitive apneas translate into oxygen partial pressure (PtO2) in brain tissue has not been studied. The objective of this study was to assess whether brain tissue is partially protected from intermittently occurring interruption of O-2 supply during recurrent swings in arterial SpO(2) in an animal model of OSA. Methods: Twenty-four male Sprague-Dawley rats (300-350 g) were used. Sixteen rats were anesthetized and noninvasively subjected to recurrent obstructive apneas: 60 apneas/h, 15 s each, for 1 h. A control group of 8 rats was instrumented but not subjected to obstructive apneas. PtO2 in the cerebral cortex was measured using a fast-response oxygen microelectrode. SpO(2) was measured by pulse oximetry. The time dependence of arterial SpO(2) and brain tissue PtO2 was carried out by Friedman repeated measures ANOVA. Results: Arterial SpO(2) showed a stable periodic pattern (no significant changes in maximum [95.5 +/- 0.5%; m +/- SE] and minimum values [83.9 +/- 1.3%]). By contrast, brain tissue PtO2 exhibited a different pattern from that of arterial SpO(2). The minimum cerebral cortex PtO2 computed during the first apnea (29.6 +/- 2.4 mmHg) was significantly lower than baseline PtO2 (39.7 +/- 2.9 mmHg; p = 0.011). In contrast to SpO(2), the minimum and maximum values of PtO2 gradually increased (p < 0.001) over the course of the 60 min studied. After 60 min, the maximum (51.9 +/- 3.9 mmHg) and minimum (43.7 +/- 3.8 mmHg) values of PtO2 were significantly greater relative to baseline and the first apnea dip, respectively. Conclusions: These data suggest that the cerebral cortex is partially protected from intermittently occurring interruption of O-2 supply induced by obstructive apneas mimicking OSA.

Keywords: Near-infrared spectroscopy, Sleep-apnea, Iintermittent hypoxia, Cerebral oxygenation, Oxidative stress, Blood-flow, Rat, Apoptosis, Inflammation, Hypercapnia