Intermittent hypoxia mobilizes hematopoietic progenitors and augments cellular and humoral elements of innate immunity in adult men

Abstract

This study tested the hypothesis that intermittent hypoxia treatment (IHT) modulates circulating hematopoietic stem and progenitor cells (HSPC) and augments humoral and cellular components of innate immunity in young, healthy men. Ten subjects (group 1: age 31±4 yr) were studied before and at 1 and 7 days after a 14-day IHT program consisting of four 5-min bouts/day of breathing 10% O2, lowering arterial O2 saturation to 84% to 85%, with intervening 5-min room-air exposures. Five more subjects (group 2: age 29±5 yr) were studied during 1 IHT session. Immunofluorescence detected HSPCs as CD45+CD34+ cells in peripheral blood. Phagocytic and bactericidal activities of neutrophils, circulating immunoglobulins (IgM, IgG, IgA), immune complexes, complement, and cytokines (erythropoietin, TNF-α, IL-4, IFN-γ) were measured. In group 1, the HSPC count fell 27% below pre-IHT baseline 1 week after completing IHT, without altering erythrocyte and reticulocyte counts. The IHT program also activated complement, increased circulating platelets, augmented phagocytic and bactericidal activities of neutrophils, sharply lowered circulating TNF-α and IL-4 by >90% and ∼75%, respectively, and increased IFN-γ, particularly 1 week after IHT. During acute IHT (group 2), HSPC increased by 51% after the second hypoxia bout and by 19% after the fourth bout, and total leukocyte, neutrophil, monocyte, and lymphocyte counts also increased; but these effects subsided by 30 min post-IHT. Collectively, these results demonstrate that IHT enhances innate immunity by mobilizing HSPC, activating neutrophils, and increasing circulating complement and immunoglobulins. These findings support the potential for eventual application of IHT for immunotherapy.

FIG. 1.

Effects of intermittent hypoxia treatment (IHT) program (A) and acute intermittent hypoxia (B) on hematopoietic stem and progenitor cells in human peripheral blood. (A) Time I: 2 weeks before IHT; time II: 1 day before IHT; time III: 1 day after the 14-day IHT program; time IV: 7 days after the IHT program. (B) Time I: 5 min before the hypoxia session; times II and III: during the final 15 to 20 s of the second and fourth hypoxia bouts, respectively; times IV and V: 15 and 30 min, respectively, after the fourth hypoxia exposure. The boxes define the lower and higher quartiles, and the bars the lowest and highest individual values from 10 (A) or 5 (B) subjects. *p<0.05 versus I; ^†p<0.05 versus II; ^‡p<0.05 versus III; **p<0.05 versus IV.

FIG. 2.

Effects of intermittent hypoxia treatment (IHT) program (A) and acute intermittent hypoxia (B) on phagocytic and bactericidal activities of blood neutrophils. Values (means±SD) are from the same subjects as in Fig. 1. Time points and significance symbols are as defined in Fig. 1. PhA, phagocytic activity; NBT-TS, NBT-test spontaneous; NBT-TI, NBT-test induced; NBT-TR, NBT-test reserve.

FIG. 3.

Effects of intermittent hypoxia treatment (IHT) on cytokine contents in human peripheral blood. (A) TNF-α, tumor necrosis factor-α; (B) IL-4, interleukin-4; (C) IFN-γ, interferon-γ; (D) EPO, erythropoietin. Times I to IV are the same as in Fig. 1A. Values are median±percentiles (boxes) and ± nonoutlier range (bars) from 10 subjects. *p<0.05 versus I; ^†p<0.05 versus II; ^‡p<0.05 versus III.