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Commentary

Hyperoxia and extrapulmonary organ injury:are the neutrophils the culprit or just innocentbystanders?

Although invasive and noninvasive continuous monitor-

ing of arterial oxygen tension has greatly contributed to the

prevention of hyperoxemia (high arterial oxygen tension),

hyperoxia (high inspired oxygen concentration) is inevitable

in subjects requiring supplemental oxygen treatment.

Continuous exposure to supplemental oxygen is known to

result in chronic lung changes characterized by arrest of

alveologenesis, airway remodeling, and pulmonary hyper-

tension [1]. That such a process is the result of an

inflammatory process is suggested by the evidence that an

increased expression of cytokines [2] and neutrophil

accumulation [3] in the lung are observed in animals

exposed to oxygen.

In the current issue, Torbati et al reported on an interesting

study addressing the effect of hyperoxia on the lungs and

extrapulmonary organs of the newborn rat. In this study, the

authors’ clearly showed that within 4 days of continuous

exposure to an Fio2 of more than 0.98 resulted in a significant

increase in blood neutrophil count, as well as intestinal

serosal and submucosal vasodilation and a mild renal tubular

necrosis. Of further interest is the authors’ observation that

after returning the chronically hyperoxic animals to room air,

the total and differential white blood cell count was

significantly elevated up to 4 days after weaning to room

air. Torbati et al speculate that chronic oxygen exposure

promotes leukocytosis and induces peripheral organ damage

independently from the lung inflammatory process.

The role of leukocytes in the mechanism of oxygen-

induced lung injury has been recently recognized. Oxygen

exposure induces leukocyte activation and sequestration in

the adult human pulmonary circulation [4]. Chronic hyper-

oxia–induced lung injury in the newborn rat is associated

with an increase in the cytokine-induced neutrophil chemo-

attractant (CINC) molecules, and CXC chemokine receptor

blockade reduces lung inflammation [5]. In addition, CINC-

1 receptor blockade prevents the arrest of alveologenesis in

newborn rats exposed to 60% oxygen chronically [3].

In the study of Torbati et al, the total circulating

neutrophils did not increase until the fourth day of oxygen

exposure. Yi et al [3], in studying newborn rats chronically

exposed to 60% oxygen, showed that, within 4 days, a

significant increase in myeloperoxidase activity was ob-

served in the lung. Together, these studies show that chronic

hyperoxia induces a significant increase in the total blood

neutrophil count, as well as an influx of these cells into the

lung likely because of an increased CINC-1 expression.

Thus, independently from the direct oxygen-induced harm-

ful effects, neutrophils are injurious to the lung likely via

generation of various reactive oxygen species.

In contrast to its usual therapeutic use, in the study of

Torbati et al, newborn animals with normal lungs were

subjected to hyperoxia, leading to concomitant hyperoxemia.

Perhaps, the most challenging question raised by the study of

Torbati et al is whether hyperoxia-activated leukocytes

induced extrapulmonary organ damage and whether this

process was triggered by the associated hyperoxemia. This is

an important clinical issue because, as opposed to hyperoxia,

hyperoxemia can be therapeutically avoided. This question,

however, remains unanswered in the study of Torbati et al.

Further investigation using protocols that allow for the study

of the distinct contribution of hyperoxia, hyperoxemia, and

Extra-pulmonary effects of hyperoxia 93

lung inflammation on peripheral organ damage is necessary

to address this important issue.

Recently, there has been a strong push toward avoiding

unnecessary exposure of neonates to hyperoxia/hyperoxemia

[6]. As such, air has been recommended instead of the

traditional use of oxygen for the resuscitation of full-term

neonates [7]. In keeping with the findings of Torbati et al in

rats, there is evidence that air resuscitation reduces peripheral

organ oxidant stress injury in neonates [8]. In addition, Vento

et al [9] have shown that neonates briefly exposed to

supplemental oxygen during resuscitation at birth demon-

strate evidence of oxidative stress at 4 weeks of age. This

finding in human neonates is in keeping with the observed

changes in white blood cells total count and abnormal weight

gain pattern in the hyperoxia-exposed newborn rats up to

4 days after weaning to room air in the study of Torbati et al.

In summary, Torbati et al have shown that chronic

hyperoxia induces changes in the total and differential

circulating white blood cells count, as well as extrapulmo-

nary organ changes lasting beyond the return of the animals

to air breathing. This study adds further weight to the

recommendation of continuing to avoid hyperoxemia and

minimizing hyperoxia, as clinically feasible.

References

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642 -7.

Jaques Belik

Division of Neonatology

Hospital for Sick Children, University of Toronto

Toronto, Ontario, Canada, M5G 1X8

E-mail address: jaques.belik@sickkids.ca

D. Torbati et al.94