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* From the Webb-Waring Institute for Cancer, Aging, and Antioxidant Research at the University of Colorado Health Sciences Center, Denver, CO.
Correspondence to: John E. Repine, MD, 4200 E Ninth Ave, Box C322, Denver, CO
ARDS remains a medical problem of considerable importance. Recent clinical trials, unfortunately, have failed to identify any therapeutic agent that has the potential of reducing the consequences of this devastating condition.
A persistent concept in the sought-after understanding of the pathogenesis of ARDS has been that an exaggerated systemic inflammatory process contributes to the pulmonary dysfunction and the multiorgan failure that subsequently characterize the syndrome. This inflammatory process is in part reflected by the increased numbers of neutrophils and increased levels of cytokines in the lung lavages of affected ARDS patients compared with control subjects. Moreover, numerous in vitro and animal studies have provided extensive evidence that suggests that neutrophils and cytokines can cause endothelial cell damage and produce lung leak abnormalities that are consistent with the lung abnormalities that occur in ARDS patients.
We became interested in determining the significance of the elevated
interleukin-1 (IL-1) levels that are manifest in the lungs of ARDS
patients compared with control subjects. Although the sources of the
increased IL-1 levels are unclear, alveolar macrophages recovered from
ARDS patients and then cultured in vitro secrete more IL-1
than alveolar macrophages recovered from control subjects. To determine
the importance of elevated IL-1 levels in the lung, we instilled IL-1
into the trachea of healthy rats.1
We found that lungs of
rats given IL-1 (50 ng) intratracheally promptly (5 h) became edematous
and that IL-1-induced lung leak was associated with increases in lung
nuclear factor-kappa B (NF-
B) activity, neutrophils, tumor necrosis
factor (TNF), cytokine-induced neutrophil chemoattractant, and
oxidative stress that was reflected by enhanced exhalation of
H2O2 and increased lung oxidized glutathione
levels. Treatment with vinblastine (neutrophil depletion), TNF binding
protein, anticytokine-induced neutrophil chemoattractant antibodies, or
various agents with antioxidant properties (superoxide dismutase,
dimethylsulfoxide, aerosolized vitamin E, N-acetylcysteine or
IL-1-receptor antagonist) decreased lung leak and indicated that IL-1
caused a neutrophil-dependent, oxidative lung leak.2
Figure 1
shows possible relationships of the findings that occur in both ARDS
patients and rats given IL-1 intratracheally.
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While it is clear that a neutrophil-mediated oxidative insult can contribute to lung injury, it is becoming evident that these processes may also participate in responses that may protect the lung against neutrophil and oxidative damage.
We and other investigators have also pursued a number of experiments that indicate that a prior oxidative stress can confer resistance or tolerance to a subsequent oxidative stress.3 4 5 6 One pertinent example is the observation that exposure of rats to sublethal concentrations of oxygen (approximately 85% O2) produces resistance to the usually fatal event that occurs following continuous exposure to 100% O2. Pretreatment with endotoxin, TNF, and/or IL-1 also produces resistance to pulmonary oxygen toxicity in rats and ischemia reperfusion-related abnormalities in isolated rat hearts.
With respect to IL-1, we found that following instillation of IL-1
intratracheally, lungs of rats that had been pretreated with IL-1 had
the same numbers of neutrophils, but developed less leak than lungs of
rats that had been pretreated with saline solution. Similarly,
following perfusion with neutrophils and IL-1 instillation
intratracheally, lungs isolated from rats that had been pretreated with
IL-1 also developed less leak than lungs isolated from rats that had
been pretreated with saline solution. In parallel, rat lung
microvascular endothelial cells (RLMECs) that had been pretreated with
IL-1 in vitro resisted injury from neutrophils stimulated by
phorbol myristate acetate better than saline solution pretreated
RLMECs. IL-1-pretreated RLMECs had increased NF-B activation
compared with saline solution pretreated RLMECs, and overexpression of
the mutant forms of IB
(S32/36A) or IBß (S19/23A)
decreased both NF-B activation and tolerance in the IL-1 pretreated
RLMECs. Therefore, in three systems, IL-1 pretreatment increased
resistance to a neutrophil-mediated, oxidant-dependent insult.
Recognizing that IL-1 can both cause and prevent neutrophil-mediated lung injury raises concerns about the design and interpretation of approaches that directly or indirectly alter IL-1 levels in these circumstances. We are attempting to decipher the mechanisms responsible for these "yin-yang" responses to IL-1 with the hope that this new information will produce insights in the treatment and prevention of ARDS (Fig 2) .
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References
-induced lung neutrophil accumulation and oxygen metabolite mediated lung leak in rats. Am J Physiol (Lung Cell Mol Physiol) 1994; 266:2–8
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