Chronic hypoxia sustained

If hypoxia is maintained, the initial microvascular responses described previously eventually resolve. In the mesenteric and cremasteric microcirculations of rats exposed to a hypoxic environment for 3 weeks, measurements of leukocyte adherence, leukocyte emigration, and vascular permeabflity are not significantly different from values obtained in animals maintained in a normal oxygen environment (i.e., normoxic animals). The mechanisms responsible for the acclimatization of vascular endothelial function during sustained hypoxia are not yet clear. However, it is well known that chronic hypoxia leads to an increase in red blood cell mass in response to increased erythropoietin secretion. It is possible that the elevated hemoglobin concentration resulting from the increased red blood cells could improve oxygen delivery to tissues and attenuate the severity of hypoxia at the venular level. However, systemic hypoxia did not result in leukocyte adherence to mesenteric venules of acclimatized rats, even after the red blood cell concentration was reduced to normal values. ... 

Cysteine proteases, called calpains, are known to be activated by sustained elevations in intracellular free calcium. Once activated, calpains degrade the cytoskeleton, transmitter and membrane channels, and metabolic enzymes (Hou and MacManus 2002 Mattson 2003 Nicholls 2004). Functionally, calpains have been characterized as pivotal mediators of both active necrotic cell death and PCD (Wang 2000) following cell-damaging stressors and insults such as soman exposure, excitotoxic challenges, toxins, free radicals, UV radiation, acute hypoxia, traumatic brain injury, cytokines, heat, and in chronic neurodegenerative conditions (Fischer et al. 1991 Caner et al. 

More importantly, the effects of theophylline are not limited to bronchodila-tion, bnt also include immunomodulatory, anti-inflammatory, and bronchoprotec-tive activity that substantially contribute to its usefulness as a prophylactic drug in asthma and other respiratory diseases. Additional effects include an increase in mucociliary clearance, a decrease of microvascular leakage into the airways, and an improvement of respiratory mnscle fatigue, especially that of the diaphragm. Theophylline fnrthermore acts centrally, blocking the decrease in ventilation that occurs with sustained hypoxia. While some of these effects are the rationale for its use in asthma, others form the basis for its effectiveness in chronic obstructive pulmonary disease (COPD) or in the treatment of apnea in premature newborns. 

Lahiri S, DiGiulio C, Roy A. Lessons from chronic intermittant and sustained hypoxia at high altitudes. Respir Physiol 2002 130 223-233. 

Chronic exposure to hypoxia after birth affects the development of the ventilatory response to hypoxia. Resetting of the chemosensitivity of the CB is delayed by hypoxia (96). Five-to-ten-week-old animals maintained under hypoxic conditions after birth show the same response to hypoxia as normoxic confrols, but this response is not sustained and exhibits a biphasic, neonatal-like pattern. Rats or cats bom in an atmosphere containing 12% O2 remain unable to respond to hypoxia (72,96). In fact, prolonged hypoxic exposure from birth increases the basal activity of the CB (72,97) and delays the onset of the chemoreflex response to hypoxia (47,72). In neonatal rats, exposure to chronic moderate hypoxia (Fi02 40.1) for 5 days leads to a subsequent desensitization of the hypoxic response that is stiU present 50 days after the exposure (94,98,99). 

Chronic sustained hypoxia leads to hypertrophy and hyperplasia of type I and II cells and angiogenesis in experimental animals as well as in humans (3,10,27,69). These... 

Numerous physiological and clinical conditions are associated with hypoxemia, ranging from acute episodes of hypoxia (asthma) to chronic sustained hypoxia (ascent to high altitude, COPD) or chronic intermittent hypoxia (OSA). During these episodes of hypoxia, activation of both peripheral and central sites likely occurs, with the net response refiecting a coordination of these drives by the pattern-generating network. 

In addition to the potential for adaptations in the eentral oxygen sensors during chronic sustained hypoxia, it is likely that adaptations occur in these central cardiorespiratory oxygen sensors during chronic intermittent hypoxia as well. Of particular interest is understanding what the impact of chronic intermittent hypoxia is on the cardiorespiratory responses and the particular adaptive or maladaptive changes in the cellular processing of the hypoxic stimulus (128-130). For example, how much of the clinical sequalae associated with OSA can be attributed to the responses to hypoxia ... 

---