S Nitrosotioles Para La Hipertension Pulmonar

S-nitrosothiol repletion by an inhaled gas regulates
pulmonary function
Martin P. Moya*, Andrew J. Gow†, Timothy J. McMahon†, Eric J. Toone‡§, Ira M. Cheifetz*, Ronald N. Goldberg*,
and Jonathan S. Stamler†§¶i
*Neonatal–Perinatal Research Institute, Department of Pediatrics; ¶Howard Hughes Medical Institute; and Departments of †Medicine, §Biochemistry, and
‡Chemistry, Duke University MedicalCenter, Durham, NC 27710
Communicated by Irwin Fridovich, Duke University Medical Center, Durham, NC, March 6, 2001 (received for review January 25, 2001)
NOsynthases are widely distributed in the lung and are extensively
involved in the control of airway and vascular homeostasis. It is
recognized, however, that the O2-rich environment of the lung
may predispose NO toward toxicity. TheseJanus faces of NO are
manifest in recent clinical trials with inhaled NO gas, which has
shown therapeutic benefit in some patient populations but increased
morbidity in others. In the airways and circulation of
humans, most NO bioactivity is packaged in the form of S-nitrosothiols
(SNOs), which are relatively resistant to toxic reactions
with O2yO2
2. This finding has led to the propositionthat channeling
of NO into SNOs may provide a natural defense against lung
toxicity. The means to selectively manipulate the SNO pool, however,
has not been previously possible. Here we report on a gas,
O-nitrosoethanol (ENO), which does not react with O2 or release
NO and which markedly increases the concentration of indigenous
species of SNO within airway lining fluid. Inhalation of ENOprovided immediate relief from hypoxic pulmonary vasoconstriction
without affecting systemic hemodynamics. Further, in a porcine
model of lung injury, there was no rebound in cardiopulmonary
hemodynamics or fall in oxygenation on stopping the drug (as
seen with NO gas), and additionally ENO protected against a
decline in cardiac output. Our data suggest that SNOs within the
lung serve inmatching ventilation to perfusion, and can be manipulated
for therapeutic gain. Thus, ENO may be of particular
benefit to patients with pulmonary hypertension, hypoxemia,
andyor right heart failure, and may offer a new therapeutic
approach in disorders such as asthma and cystic fibrosis, where the
airways may be depleted of SNOs.
The airways and blood vessels of the lung, the nerves thatinnervate these structures, and the cells that reside within
them are enriched in three major isoforms ofNOsynthase (NOS;
refs. 1 and 2). A high level of NOS expression is already evident
in the developing fetus and plays a key role in the transition from
fetal to adult circulation (3). Vascular NOSs function to maintain
normoxic pulmonary vascular tone and to counter hypoxic
pulmonaryvasoconstriction; NOS up-regulation by hypoxia
further serves to protect against pulmonary hypertension and
right heart failure (4). NOSs may have additional homeostatic
roles in the airway, including control of bronchial tone, mucus
secretion, sodiumywater permeability, ciliary motility, and in
defense against pathogens and pollutants.
There is now considerable evidence to indicate that highconcentrations of NO can be toxic (1, 5–7) and that O2-rich
environments such as the lung are particularly predisposed to its
potentially mutagenic (8), proapoptotic (9) and proinflammatory
properties (5). These findings are well rationalized by the
chemical reactions of NO with O2 and reactive oxygen species,
which yield higher oxides of nitrogen (NOx) that can cause
inflammation, hemorrhage, andedema (1). In particular, the
airways of subjects administered inhaled NO gas reveal the same
footprints of oxidative injury that are found in animals and
humans exposed to NOx or hyperoxia (10, 11), and various NOx
have been implicated in pollutant-induced asthma (12) and in
‘‘silo fillers’ lung’’ (a potentially fatal disorder; ref. 13). However,
endogenous NOSs do not generate high levels...