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Ischemia has elicited a great deal of interest among the scientific community due to its role in life-threatening pathologies such as cancer, stroke, acute renal failure, and myocardial infarction. Oxygen deprivation (hypoxia) associated with ischemia has recently become a subject of intense scrutiny. New investigators may find it challenging to induce hypoxic injury in vitro. Researchers may not always be aware of the experimental barriers that contribute to this phenomenon. Furthermore, ischemia is associated with other major insults, such as excess carbon dioxide (hypercapnia), nutrient deprivation, and accumulation of cellular wastes. Ideally, these conditions should also be incorporated into in vitro models. Therefore, the motivation behind this review is to: i. delineate major in vivo ischemic insults; ii. identify and explain critical in vitro parameters that need to be considered when simulating ischemic pathologies; iii. provide recommendations to improve experiments; and as a result, iv. enhance the validity of in vitro results for understanding clinical ischemic pathologies. Undoubtedly, it is not possible to completely replicate the in vivo environment in an ex vivo model system. In fact, the primary goal of many in vitro studies is to elucidate the role of specific stimuli during in vivo pathological events. This review will present methodologies that may be implemented to improve the applicability of in vitro models for understanding the complex pathological mechanisms of ischemia. Finally, although these topics will be discussed within the context of renal ischemia, many are pertinent for cellular models of other organ systems and pathologies.
Exp Mol Pathol 2007 Oct
PMID:Experimental strategies to improve in vitro models of renal ischemia. 1749 Jun 40

Carbonic anhydrase II (CAII) plays an important role in carbon dioxide metabolism and intracellular pH regulation. In this study, we provide evidence that CAII is expressed in both type I (AECI) and type II (AECII) alveolar epithelial cells by RT-PCR and Western blotting in freshly isolated rat cells. These results were further confirmed by double immunostaining with CAII antibodies and AECI- or AECII-specific markers in freshly isolated alveolar epithelial cells and rat lung tissues. Inhibition of CAII by acetazolamide or methazolamide delayed the decrease in the intracellular pH observed during hypercapnia in cultured AECI, AECII, and AECI-like cells. In an isolated-perfused rat lung model, alveolar fluid reabsorption significantly decreased during high CO(2) exposure, which was not prevented by carbonic anhydrase inhibition. Thus, we provide evidence that CAII is expressed in rat alveolar epithelial cells and does not regulate lung alveolar fluid reabsorption during hypercapnia.
Am J Respir Cell Mol Biol 2008 Jan
PMID:Carbonic anhydrase II and alveolar fluid reabsorption during hypercapnia. 1855 9

Common responses to hypoxia include decreased body temperature (Tb) and decreased energy metabolism. In this study, the effects of hypoxia and hypercapnia on Tb and metabolic oxygen consumption (VO2) were investigated in Japanese quail (Coturnix japonica). When exposed to hypoxia (15, 13, 11 and 9% O2), Tb decreased only at 11% and 9% O2 compared to normoxia; quail were better able to maintain Tb during acute hypoxia after a one-week acclimation to 10% O2. VO2 also decreased during hypoxia, but at 9% O2 this was partially offset by increased anaerobic metabolism. Tb and VO2 responses to 9% O2 were exaggerated at lower ambient temperature (Ta), reflecting a decreased lower critical temperature during hypoxia. Conversely, hypoxia had little effect on T(b) or VO2 at higher Ta (36 degrees C). We conclude that Japanese quail respond to hypoxia in much the same way as mammals, by reducing both Tb and VO2. No relationship was found between the magnitudes of decreases in Tb and VO2 during 9% O2, however. Since metabolism is the source of heat generation, this suggests that Japanese quail increase thermolysis to reduce Tb. During hypercapnia (3, 6 and 9% CO2), Tb was reduced only at 9% CO2 while VO2 was unchanged.
Comp Biochem Physiol A Mol Integr Physiol 2008 Dec
PMID:Thermoregulatory and metabolic responses of Japanese quail to hypoxia. 1872 57

This article highlights studies published during the past year that represent significant scientific achievements in the world of calmodulin kinase cascades. Calmodulin is the primary receptor for calcium present in all cells. The binding of its calcium ligand results in a conformational change in calmodulin, which allows the calcium-calmodulin complex to interact with many different targets. In the studies to be summarized in this review, the particular calmodulin cascade involved is shown to be the pathway responsible for important biological responses, including long-term memory formation, dendritic cell survival, hypercapnia, neuronal migration, synapse formation, autophagy, fatty acid oxidation, and energy balance. In some cases, the pathway was previously unknown, and the identification of the calmodulin cascade represents the definition of roles. In other cases, manipulating the cascade has suggested therapeutic approaches to certain diseases, most significantly, type 2 diabetes and obesity.
Mol Endocrinol 2008 Dec
PMID:The Year in Basic Science: calmodulin kinase cascades. 1884 71

We measured the effects of raising perfusate pH on ventilator-induced cell wounding and repair in ex vivo mechanically ventilated hypercapnic rat lungs. Lungs were randomized to one of three perfusate groups: 1) unbuffered hypercapnic acidosis, 2) bicarbonate-buffered hypercapnia, or 3) tris-hydroxymethyl aminomethane (THAM)-buffered hypercapnia. The membrane-impermeant label propidium iodide was added to the perfusate either during or after injurious ventilation providing a means to subsequently identify transiently wounded and permanently wounded cells in optical sections of subpleural alveoli. Normalizing perfusate pH in hypercapnic preparations attenuated ventilator-induced cell injury, particularly in THAM-buffered preparations. This was observed despite greater amounts of edema and impaired lung mechanics compared with other treatment groups. Protective effects of buffering of hypercapnic acidosis on injury and repair were subsequently confirmed in a cell scratch model. We conclude that buffering of hypercapnic acidosis attenuates plasma cell injury induced by mechanical hyperinflation.
Am J Physiol Lung Cell Mol Physiol 2009 Jan
PMID:Impact of buffering hypercapnic acidosis on cell wounding in ventilator-injured rat lungs. 1899 1

In rats, chronic hypercapnia has been reported to ameliorate hypoxia-induced pulmonary hypertension in newborn and adult and to enhance endothelium-dependent vasorelaxation in adult pulmonary arteries. The underlying mechanisms accounting for chronic hypercapnia-induced improvements in pulmonary vascular function are not understood. Hypothesizing that downregulation of arginase activity may be contributory, we examined relaxation responses and arginase activity and expression in pulmonary arteries from newborn rats that were exposed (from birth to 14 days) to either mild-to-moderate (5.5% inhaled CO(2)) or severe (10% CO(2)) hypercapnia with either normoxia or hypoxia (13% O(2)). Pulmonary arteries from pups exposed to normoxia and chronic hypercapnia (5.5 or 10% CO(2)) contracted less in response to a thromboxane A(2) analog, U-46619, and showed enhanced endothelium-dependent (but not independent) relaxation compared with arteries from normocapnic pups (P < 0.01). Parallel with these changes, arginase activity and arginase I (but not II) expression in lung and pulmonary arterial tissue were significantly decreased (P < 0.05). Exposure to 10% CO(2) significantly increased (P < 0.01) pulmonary arterial tissue nitric oxide (nitrite) generation. In pups chronically exposed to hypoxia (13% O(2)), severe hypercapnia (10% CO(2)) significantly (P < 0.05) enhanced endothelium-dependent relaxation, increased nitric oxide generation, and decreased arginase activity but not expression. We conclude that chronic hypercapnia-induced downregulation of lung arginase expression and/or activity may reduce pulmonary vascular resistance by enhancing nitric oxide generation and thus endothelium-dependent relaxation. This mechanism may explain some of the beneficial effects of chronic hypercapnia on experimental pulmonary hypertension.
Am J Physiol Lung Cell Mol Physiol 2009 Oct
PMID:Chronic hypercapnia downregulates arginase expression and activity and increases pulmonary arterial smooth muscle relaxation in the newborn rat. 1966 77

High tidal volume ventilation is detrimental to alveolar fluid clearance (AFC), but effects of ventilation pressure (P) on AFC are unknown. In anesthetized BALB/c mice ventilated at constant tidal volume (8 ml/kg), mean AFC rate was 12.8% at 6 cmH(2)O P, but increased to 37.3% at 18 cmH(2)O P. AFC rate declined at 22 cmH(2)O P, which also induced lung damage. Increased AFC at 18 cmH(2)O P did not result from elevated plasma catecholamines, hypercapnia, or hypocapnia, but was due to augmented Na(+) and Cl(-) absorption. PKA agonists and beta-agonists stimulated AFC at 10 cmH(2)O P by upregulating amiloride-sensitive Na(+) transport. However, at 18 cmH(2)O P, PKA agonists and beta-agonists reduced AFC. At 15 cmH(2)O P, the AFC rate was intermediate (mean 26.6%), and forskolin and beta-agonists had no effect. Comparable P dependency of AFC and beta-agonist responsiveness was found in C57BL/6 mice. The effect on AFC of increasing P to 18 cmH(2)O was blocked by adenosine deaminase or an A(2b)-adenosine receptor antagonist, and could be mimicked by adenosine in mice ventilated at 10 cmH(2)O P. Modulation of adenosine signaling also resulted in altered responsiveness to beta-agonists. These findings indicate that, in the normal mouse lung, basal AFC rates and responses to beta-agonists are impacted by ventilation pressure in an adenosine-dependent manner.
Am J Physiol Lung Cell Mol Physiol 2009 Oct
PMID:Effect of ventilation pressure on alveolar fluid clearance and beta-agonist responses in mice. 1968 2

Acute respiratory disorders and permissive hypercapnic strategy may lead to alveolar hypoxia and hypercapnic acidosis. However, the effects of hypercapnia with or without acidosis on hypoxic pulmonary vasoconstriction (HPV) and oxygen diffusion capacity of the lung are controversial. We investigated the effects of hypercapnic acidosis and hypercapnia with normal pH (pH corrected with sodium bicarbonate) on HPV, capillary permeability, gas exchange, and ventilation-perfusion matching in the isolated ventilated-perfused rabbit lung. No alteration in vascular tone was noted during normoxic hypercapnia with or without acidosis compared with normoxic normocapnia. Hypercapnia with normal pH resulted in a transient increase in HPV during the course of consecutive ventilation maneuvers, whereas hypercapnic acidosis increased HPV over time. Hypercapnic acidosis decreased exhaled NO during hypoxia more than hypercapnia with normal pH and normocapnia, whereas intravascular NO release was unchanged. However, inhibition of NO synthesis by nitro-L-arginine (L-NNA) resulted in a loss of the increased HPV caused by hypercapnic acidosis but not that caused by hypercapnia with normal pH. Furthermore, capillary permeability increased during hypoxic hypercapnia with normal pH but not hypoxic hypercapnic acidosis. This effect was NO-dependent because it disappeared during L-NNA administration. Ventilation-perfusion matching and arterial PO2 were improved according to the strength of HPV in hypercapnia compared with normocapnia during Tween nebulization-induced lung injury. In conclusion, the increased HPV during hypercapnic acidosis is beneficial to lung gas exchange by improving ventilation-perfusion matching and preserving the capillary barrier function. These effects seem to be linked to NO-mediated pathways.
Am J Physiol Lung Cell Mol Physiol 2009 Nov
PMID:Effects of hypercapnia with and without acidosis on hypoxic pulmonary vasoconstriction. 1971 54

Permissive hypercapnia, achieved using low tidal volume ventilation, has been an effective protective strategy in patients with acute respiratory distress syndrome. To date, no such protective effect has been demonstrated for the chronic neonatal lung injury, bronchopulmonary dysplasia. The objective of our study was to determine whether evolving chronic neonatal lung injury, using a rat model, is resistant to the beneficial effects of hypercapnia or simply requires a less conservative approach to hypercapnia than that applied clinically to date. Neonatal rats inhaled air or 60% O2 for 14 days with or without 5.5% CO2. Lung parenchymal neutrophil and macrophage numbers were significantly increased by hyperoxia alone, which was associated with interstitial thickening and reduced secondary crest formation. The phagocyte influx, interstitial thickening, and impaired alveolar formation were significantly attenuated by concurrent hypercapnia. Hyperoxic pups that received 5.5% CO2 had a significant increase in alveolar number relative to air-exposed pups. Increased tyrosine nitration, a footprint for peroxynitrite-mediated reactions, arteriolar medial wall thickening, and both reduced small peripheral pulmonary vessel number and VEGF and angiopoietin-1 (Ang-1) expression, which were observed with hyperoxia, was attenuated by concurrent hypercapnia. We conclude that evolving chronic neonatal lung injury in a rat model is responsive to the beneficial effects of hypercapnia. Inhaled 5.5% CO2 provided a significant degree of protection against parenchymal and vascular injury in an animal model of chronic neonatal lung injury likely due, at least in part, to its inhibition of a phagocyte influx.
Am J Physiol Lung Cell Mol Physiol 2009 Nov
PMID:Therapeutic effects of hypercapnia on chronic lung injury and vascular remodeling in neonatal rats. 1974

Carbon dioxide (CO(2)) is an important gaseous molecule that maintains biosphere homeostasis and is an important cellular signalling molecule in all organisms. The transport of CO(2) through membranes has fundamental roles in most basic aspects of life in both plants and animals. There is a growing interest in understanding how CO(2) is transported into cells, how it is sensed by neurons and other cell types and in understanding the physiological and molecular consequences of elevated CO(2) levels (hypercapnia) at the cell and organism levels. Human pulmonary diseases and model organisms such as fungi, C. elegans, Drosophila and mice have been proven to be important in understanding of the mechanisms of CO(2) sensing and response.
J Cell Mol Med
PMID:Sensing, physiological effects and molecular response to elevated CO2 levels in eukaryotes. 1986 92


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