# NITRIC OXIDE SYNTHESIS IN THE PULMONARY CIRCULATION

> **NIH NIH R01** · UNIV OF NORTH CAROLINA CHAPEL HILL · 1994 · $218,334

## Abstract

The induced synthesis of NO in response to cytokine stimulation contrasts
with its constitutive release in picomolar (pM) quantities for a few
seconds as an endothelium dependent mediator of vascular relaxation.
Stimulated by inflammatory mediators such as E.  coli lipopolysaccharide
(LPS), tumor necrosis factor (TNFa), and interferon gamma (IFNg), an
inducible NOS (iNOS) present in vascular smooth muscle and endothelium
releases NO in uM quantities for up to 48 hours.  Cytokine induced
production of NO may have exaggerated effects on vascular reactivity and
may be cytotoxic. The induced production of NO in the lung may have
pathophysiologic relevance to acute lung injury and adult respiratory
distress syndrome (ARDS).  Preliminary studies indicate that a mixture of
LPS and cytokines, TNFa and IFNg in particular, stimulate rat pulmonary
artery smooth muscle (RPASM) cells in culture to increase NO production in
a time and tetrahydrobiopter (BH4) dependent manner, with increased mRNA
levels for iNOS and GTP cyclohydrolase (GTP-CH), the rate limiting enzyme
in the production of BH4.  NO, either released from an NO generating
compound or from stimulated RPASM in coculture, appears to be cytotoxic
for endothelial target cells.  The applicants' findings led to the overall
hypothesis that the inappropriate vascular lability and endothelial
dysfunction seen in lung during sepsis is in part the result of NO release
by vascular smooth muscle and endothelium. The up regulation of iNOS and
GTP-CH results from enzyme induction by inflammatory cytokines,
principally TNFa and IFNg. Accordingly, aim (1) is to define the
mechanisms underlying TNFa and IFNg induced NO production by RPASM and
endothelium (RPAE) in cell culture.  Aim 2 is to determine the effects of
cytokine induced, smooth muscle and endothelial derived NO on (a) the
reactivity of pulmonary vascular rings; and (b) the maintenance of oxidant
sensitive endothelial functions.  The relationship between iNOS expression
and cytotoxicity will be established by antisense inhibition to iNOS and
GTP-CH expression.

## Key facts

- **NIH application ID:** 2190685
- **Project number:** 1R01GM051905-01
- **Recipient organization:** UNIV OF NORTH CAROLINA CHAPEL HILL
- **SAM.gov UEI:** D3LHU66KBLD5
- **Principal Investigator:** DON K NAKAYAMA
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 1994
- **Award amount:** $218,334
- **Award type:** 1
- **Project period:** 1994-04-01 → 1997-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/2190685

## Citation

> US National Institutes of Health, RePORTER application 2190685, NITRIC OXIDE SYNTHESIS IN THE PULMONARY CIRCULATION (1R01GM051905-01). Retrieved via MORVS 2026-10-24 from https://api.morvs.ai/grant/nih/2190685. Licensed CC0.

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