The Nobel Mabel. The woman who discovered that low oxygen stimulates hemoglobin production.

The research of Mabel Purefoy FitzGerald (1872-1973) was recently recognized by Sir Peter Ratcliffe in his public lecture at the awarding of the Nobel Prize in Physiology or Medicine as a critical step in the recent delineation of the oxygen sensing pathway. This brief article offers a tantalizing glimpse into the life of a woman whose scientific career spanned four countries, worked with eminent scientists and clinicians including Haldane and Osler, and published important physiologic discoveries. Her accomplishments and astounding life were lost to history for more than one hundred years and it is time to bring her back. When this diminutive and proper English woman set out on her own to the wild and remote mining towns of Colorado, little did she know that this would be the moment for which she would be remembered in her long, productive research career and ludicrous struggle to become a physician more than a century ago. Hers is an extraordinary tale of privilege, hardship, discrimination, shocking perseverance, and grand adventure.

The hypoxic placenta.

Hypoxia of the placenta is integral to complications of pregnancy, including preeclampsia, intrauterine growth restriction, and small-for-gestational age babies. Hypoxia in the placenta is associated with vascular remodeling, hypertension, metabolic changes, oxidative stress, mitochondrial dysfunction, and endoplasmic reticular stress. Hypoxia induces similar outcomes in other organs such as the lungs, kidney, and gut. Comparing and contrasting the effects of hypoxia on placental functions and functions of lung, kidney, and gut can lead to novel hypotheses and investigations, furthering our understanding of the impact of hypoxia on these diverse yet similar organs. In this review, we compare and contrast hypoxic placental responses to those in the other organ and cell systems.

Hypoxia: adapting to high altitude by mutating EPAS-1, the gene encoding HIF-2α.

Living at high altitude is demanding and thus drives adaptational mechanisms. The Tibetan population has had a longer evolutionary period to adapt to high altitude than other mountain populations such as Andeans. As a result, some Tibetans living at high altitudes do not show markedly elevated red blood cell production as compared to South American high altitude natives such as Quechuas or Aymaras, thereby avoiding high blood viscosity creating cardiovascular risk. Unexpectedly, the responsible mutation(s) reducing red blood cell production do not involve either the gene encoding the blood hormone erythropoietin (Epo), or the corresponding regulatory sequences flanking the Epo gene. Similarly, functional mutations in the hypoxia-inducible transcription factor 1α (HIF-1α) gene that represents the oxygen-dependent subunit of the HIF-1 heterodimer, the latter being the main regulator of over 100 hypoxia-inducible genes, have not been described so far. It was not until very recently that three independent groups showed that the gene encoding HIF-2α, EPAS-1 (Wenger et al. 1997), represents a key gene mutated in Tibetan populations adapted to living at high altitudes (Beall et al. 2010 , Yi et al. 2010 , Simonson et al. 2010). Hypoxia-inducible transcription factors were first identified by the description of HIF-1 (Semenza et al. 1991 , 1992), which was subsequently found to enhance transcription of multiple genes that encode proteins necessary for rescuing from hypoxic exposure, including erythropoietic, angiogenic and glycolytic proteins. Then HIF-2 was identified (Ema et al. 1997 ; Flamme et al. 1997 ; Hogenesch et al. 1997 ; and Tian et al. 1997) and although it is highly similar to HIF-1 and has the potential to bind (Camenisch et al. 2001) and mediate (Mole et al. 2009) many of the same genes as HIF-1, its biological actions in response to hypoxia are distinct from those of HIF-1 (reviewed by Loboda et al. 2010). By now, several of these HIF-2 mediated processes have been implicated in the human response to high altitude exposure including erythropoiesis (Kapitsinou et al. 2010), iron homeostasis (Peyssonnaux et al. 2008), metabolism (Shohet et al. 2007; Tormos et al. 2010; Biswas et al. 2010 ; Rankin et al. 2009) and vascular permeability (Chen et al. 2009; Tanaka et al. 2005), among others. Clearly, mutation of EPAS-1 has the potential to bring far more advantage when adapting to high altitude than solely mutating the Epo gene.

A potential role for reactive oxygen species and the HIF-1alpha-VEGF pathway in hypoxia-induced pulmonary vascular leak.

Acute hypoxia causes pulmonary vascular leak and is involved in the pathogenesis of pulmonary edema associated with inflammation, acute altitude exposure, and other critical illnesses. Reactive oxygen species, HIF-1, and VEGF have all been implicated in various hypoxic pathologies, yet the ROS-HIF-1-VEGF pathway in pulmonary vascular leak has not been defined. We hypothesized that the ROS-HIF-1-VEGF pathway has an important role in producing hypoxia-induced pulmonary vascular leak. Human pulmonary artery endothelial cell (HPAEC) monolayers were exposed to either normoxia (21% O(2)) or acute hypoxia (3% O(2)) for 24 h and monolayer permeability and H(2)O(2), nuclear HIF-1alpha, and cytosolic VEGF levels were determined. HPAEC were treated with antioxidant cocktail (AO; ascorbate, glutathione, and alpha-tocopherol), HIF-1 siRNA, or the VEGF soluble binding protein fms-like tyrosine kinase-1 (sFlt-1) to delineate the role of the ROS-HIF-1-VEGF pathway in hypoxia-induced HPAEC leak. Additionally, mice exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) were treated with the same antioxidant to determine if in vitro responses corresponded to in vivo hypoxia stress. Hypoxia increased albumin permeativity, H(2)O(2) production, and nuclear HIF-1alpha and cytosolic VEGF concentration. Treatment with an AO lowered the hypoxia-induced HPAEC monolayer permeability as well as the elevation of HIF-1alpha and VEGF. Treatment of hypoxia-induced HPAEC with either an siRNA designed against HIF-1alpha or the VEGF antagonist sFlt-1 decreased monolayer permeability. Mice treated with AO and exposed to hypobaric hypoxia (18,000 ft, 10% O(2)) had less pulmonary vascular leak than those that were untreated. Our data suggest that hypoxia-induced permeability is due, in part, to the ROS-HIF-1alpha-VEGF pathway.

Glutaraldehyde-polymerized bovine hemoglobin and phosphodiesterase-5 inhibition.

OBJECTIVE: Hemoglobin-based oxygen carriers (HBOC) of several types scavenge nitric oxide from the vasculature resulting in vasoconstriction and hypertension, both systemic and pulmonary. Phosphodiesterase-5 (PDE5) inhibitors promote nitric oxide activity and enhance vasodilation. The purpose of this study was to determine whether combined therapy of glutaraldehyde-polymerized bovine hemoglobin (HBOC) with a PDE5 inhibitor would counter the negative hemodynamic consequences of HBOC therapy alone, resulting in improved hemodynamics and oxygen delivery. DESIGN: A controlled, experimental study. SETTING: A research laboratory at a university. SUBJECTS: Conscious male Sprague-Dawley rats. INTERVENTIONS: Glutaraldehyde-polymerized bovine hemoglobin (HBOC), sildenafil (PDE5 inhibitor), and lactated Ringer's solution (control). MEASUREMENTS AND MAIN RESULTS: Infusion of the HBOC resulted in significant (p < 0.05) systemic and pulmonary vasoconstriction, with reduced cardiac output and reduced oxygen delivery to the periphery. Infusion of lactated Ringer's demonstrated no changes in the measured variables. Infusion of sildenafil alone reduced systemic and pulmonary artery blood pressure, while maintaining cardiac output and oxygen delivery. Combined HBOC and sildenafil infusion resulted in stable systemic blood pressure, cardiac output, and oxygen delivery. However, the addition of sildenafil to HBOC did not fully ameliorate the pulmonary vasoconstriction caused by HBOC. CONCLUSION: The HBOC used in this study resulted in pulmonary and systemic hypertension, reduced cardiac output, and oxygen delivery. These negative consequences of HBOC treatment can be largely overcome by combing HBOC treatment with a PDE5 inhibitor (sildenafil). Thus, these data support the continued investigation of combined HBOC and PDE5 inhibitor treatment in circumstances in which HBOC therapy is being considered.

Ginkgo biloba for prevention of acute mountain sickness: does it work?

Tissot van Patot, Martha, Linda E. Keyes, Guy Leadbetter III, and Peter H. Hackett. Ginkgo biloba for the prevention of acute mountain sickness: does it work? High Alt. Med. Biol. 10:00-00, 2009.-We review the current literature regarding the prophylactic use of Ginkgo biloba extract (GBE) in acute mountain sickness (AMS). We compare studies with regard to GBE dose, composition, study design, altitude reached, ascent rate, exercise, and risk of AMS. We then review what is known about the active components of GBE and their biological effects and apply this knowledge to interpret the results of AMS prevention trials. Overall, the literature suggests that due to the complexity of GBE the standardization of the product is inadequate, which likely explains the disparate clinical results. The variability in commercially available GBE products makes it impossible to determine whether GBE is truly effective for preventing or ameliorating AMS. However, investigating the roles of specific active components of GBE in the prevention of AMS could yield rewards both clinically and in our understanding of the pathophysiology of AMS.

Prophylactic low-dose acetazolamide reduces the incidence and severity of acute mountain sickness.

Previous studies have shown low-dose acetazolamide to be effective in preventing AMS in persons already at high altitude and then moving higher, a relatively low risk situation. We wished to evaluate prophylactic administration of low-dose acetazolamide for reducing the incidence and severity of AMS in a high-risk setting: rapid ascent from 1600 to 4300 m. We performed a double-blind, randomized, placebo-controlled study with human subjects (n=44) exposed to 4300 m for 24 h. Subjects were treated for 3 days prior to ascent to 4300 m and during day 1 at altitude with placebo (n=22) or acetazolamide 250 mg/day (125 mg bid, n=22). AMS diagnosis required both an AMS-C score from the Environmental Symptom Questionnaire-III>or=0.7 and a Lake Louise Symptom (LLS) questionnaire score>or=3 plus headache. Acetazolamide reduced the incidence of AMS compared to placebo-treated subjects (14% vs. 45%, respectively, p=0.02), and the number needed to treat was 3. The AMS-C and LLS scores were lower in acetazolamide-treated subjects, indicating less severe AMS. Low-dose acetazolamide administered prior to ascent and on day 1 at 4300 m effectively reduced the incidence and severity of AMS in a high-risk setting.

Risk of impaired coagulation in warfarin patients ascending to altitude (>2400 m).

Approximately 476,000 people on warfarin therapy visit a resort at altitude (>2400 m) annually in Colorado. Clinicians practicing at altitude have expressed concern that ascent to altitude adversely affects coagulation in patients taking warfarin in both high altitude residents and visitors. We sought to determine the effect of ascent to and descent from altitude on coagulation in warfarin patients, as assessed by the international normalized ratio (INR). A retrospective medical chart review was conducted on all warfarin patients treated between August 1998 and October 2003 at a cardiology clinic in which travel to and from altitude was documented in association with each INR measurement in high altitude residents. Of the 1139 INR measurements in 49 patients, 143 were associated with changes in altitude (in 32 of 49 patients). The odds of an INR measurement being below the prescribed range were 2.7 times (95% CI: 1.2-5.8) higher among warfarin patients with recent ascent to altitude, 2.1 times (95% CI: 1.4-3.2) higher among warfarin patients with atrial fibrillation, and 5.6 (95% CI: 2.3-13.7) times higher among warfarin patients with both atrial fibrillation and recent ascent to altitude. Increasing altitude is a risk factor for subtherapeutic INR in warfarin patients and this risk is doubled in atrial fibrillation patients.