The hypoxia-inducible factor (HIF) family of transcription factors directs a coordinated cellular response to hypoxia that includes the transcriptional regulation of a number of metabolic enzymes. Chuvash polycythemia (CP) is an autosomal recessive human disorder in which the regulatory degradation of HIF is impaired, resulting in elevated levels of HIF at normal oxygen tensions. Apart from the polycythemia, CP patients have marked abnormalities of cardiopulmonary function. No studies of integrated metabolic function have been reported. Here we describe the response of these patients to a series of metabolic stresses: exercise of a large muscle mass on a cycle ergometer, exercise of a small muscle mass (calf muscle) which allowed noninvasive in vivo assessments of muscle metabolism using ³¹ P magnetic resonance spectroscopy, and a standard meal tolerance test. During exercise, CP patients had early and marked phosphocreatine depletion and acidosis in skeletal muscle, greater accumulation of lactate in blood, and reduced maximum exercise capacities. Muscle biopsy specimens from CP patients showed elevated levels of transcript for pyruvate dehydrogenase kinase, phosphofructokinase, and muscle pyruvate kinase. In cell culture, a range of experimental manipulations have been used to study the effects of HIF on cellular metabolism. However, these approaches provide no potential to investigate integrated responses at the level of the whole organism. Although CP is relatively subtle disorder, our study now reveals a striking regulatory role for HIF on metabolism during exercise in humans. These findings have significant implications for the development of therapeutic approaches targeting the HIF pathway.

Key Points: Neutrophil lifespan is extended in patients with gain-of-function HIF2A mutations. HIF-2α regulates in vivo neutrophil longevity and thus tissue inflammation and repair.

Tibetan natives have lived on the Tibetan plateau (altitude ∼4,000 m) for at least 25,000 years, and as such they are adapted to life and reproduction in a hypoxic environment. Recent studies have identified two genetic loci, EGLN1 and EPAS1, that have undergone natural selection in Tibetans, and further demonstrated an association of EGLN1/EPAS1 genotype with hemoglobin concentration. Both genes encode major components of the hypoxia-inducible factor (HIF) transcriptional pathway, which coordinates an organism's response to hypoxia. Patients living at sea level with genetic disease of the HIF pathway have characteristic phenotypes at both the integrative-physiology and cellular level. We sought to test the hypothesis that natural selection to hypoxia within Tibetans results in related phenotypic differences. We compared Tibetans living at sea level with Han Chinese, who are Tibetans' most closely related major ethnic group. We found that Tibetans had a lower hemoglobin concentration, a higher pulmonary ventilation relative to metabolism, and blunted pulmonary vascular responses to both acute (minutes) and sustained (8 h) hypoxia. At the cellular level, the relative expression and hypoxic induction of HIF-regulated genes were significantly lower in peripheral blood lymphocytes from Tibetans compared with Han Chinese. Within the Tibetans, we found a significant correlation between both EPAS1 and EGLN1 genotype and the induction of erythropoietin by hypoxia. In conclusion, this study provides further evidence that Tibetans respond less vigorously to hypoxic challenge. This is evident at sea level and, at least in part, appears to arise from a hyporesponsive HIF transcriptional system.

The hypoxia‐inducible factors (HIFs; isoforms HIF‐1α, HIF‐2α, HIF‐3α) mediate many responses to hypoxia. Their regulation is principally by oxygen‐dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel‐Lindau (VHL) protein. Chuvash polycythe‐mia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF‐2α gain‐of‐function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF‐2α gain‐of‐function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF‐2α gain‐of‐function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild‐type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF‐2α gain‐of‐function phenotype may be more limited than the Chuvash phenotype either because HIF‐1α is not elevated in the former condition, or because other HIF‐independent functions of VHL are perturbed in Chuvash polycythemia.—Formenti, F., Beer, P. A., Croft, Q. P. P., Dorrington, K. L., Gale, D. P., Lappin, T. R J., Lucas, G. S., Maher, E. R, Maxwell, P. H., McMullin, M. F., O'Connor, D. F., Percy, M. J., Pugh, C. W., Ratcliffe, P. J., Smith, T. G., Talbot, N. P., Robbins, P. A. Cardiopulmonary function in two human disorders of the hypoxia‐inducible factor (HIF) pathway: von Hippel‐Lindau disease and HIF‐2α gain‐of‐function mutation. FASEB J. 25, 2001‐2011 (2011). www.fasebj.org

New Findings: What is the topic of this review? This review presents the fundamental concepts of respiratory physiology and pathophysiology, with particular reference to lung mechanics and the pulmonary phenotype associated with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection and subsequent coronavirus disease 2019 (COVID‐19) pneumonia. What advances does it highlight? The review provides a critical summary of the main physiological aspects to be considered for safe and effective mechanical ventilation in patients with severe COVID‐19 in the intensive care unit. Severe respiratory failure from coronavirus disease 2019 (COVID‐19) pneumonia not responding to non‐invasive respiratory support requires mechanical ventilation. Although ventilation can be a life‐saving therapy, it can cause further lung injury if airway pressure and flow and their timing are not tailored to the respiratory system mechanics of the individual patient. The pathophysiology of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection can lead to a pattern of lung injury in patients with severe COVID‐19 pneumonia typically associated with two distinct phenotypes, along a temporal and pathophysiological continuum, characterized by different levels of elastance, ventilation‐to‐perfusion ratio, right‐to‐left shunt, lung weight and recruitability. Understanding the underlying pathophysiology, duration of symptoms, radiological characteristics and lung mechanics at the individual patient level is crucial for the appropriate choice of mechanical ventilation settings to optimize gas exchange and prevent further lung injury. By critical analysis of the literature, we propose fundamental physiological and mechanical criteria for the selection of ventilation settings for COVID‐19 patients in intensive care units. In particular, the choice of tidal volume should be based on obtaining a driving pressure < 14 cmH₂O, ensuring the avoidance of hypoventilation in patients with preserved compliance and of excessive strain in patients with smaller lung volumes and lower lung compliance. The level of positive end‐expiratory pressure (PEEP) should be informed by the measurement of the potential for lung recruitability, where patients with greater recruitability potential may benefit from higher PEEP levels. Prone positioning is often beneficial and should be considered early. The rationale for the proposed mechanical ventilation settings criteria is presented and discussed.