Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice

Elena N. Atochina-Vasserman, Michael F. Beers, Helchem Kadire, Yaniv Tomer, Adam Inch, Pamela Scott, Chang J. Guo, Andrew J. Gow

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Surfactant protein D (SP-D)-deficient (SP-D-/-) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1% of saline-treated 10-wk-old SP-D-/- littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-γ) seen in bronchoalveolar lavage (BAL) of SP-D-/- mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3% of saline-treated SP-D-/- mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D-/- mice as shown by decreases in total BAL cell count (63 ± 6% of SP-D-/- control), macrophage size (>25 μm) within the BAL (62 ± 10% of SP-D-/- control), and a percentage of BAL macrophages producing oxidants (76 ± 9% of SP-D-/- control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.

Original languageEnglish
Pages (from-to)8090-8097
Number of pages8
JournalJournal of Immunology
Volume179
Issue number12
Publication statusPublished - 15 Dec 2007
Externally publishedYes

Fingerprint

Pulmonary Surfactant-Associated Protein D
Nitric Oxide Synthase
Bronchoalveolar Lavage
Protein Deficiency
Lung
Pneumonia
Chemokine CCL17
Macrophages
Matrix Metalloproteinase 2
Matrix Metalloproteinase 9
Emphysema
Oxidants
Immune System
Homeostasis
Therapeutics
Cell Count

ASJC Scopus subject areas

  • Immunology

Cite this

Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice. / Atochina-Vasserman, Elena N.; Beers, Michael F.; Kadire, Helchem; Tomer, Yaniv; Inch, Adam; Scott, Pamela; Guo, Chang J.; Gow, Andrew J.

In: Journal of Immunology, Vol. 179, No. 12, 15.12.2007, p. 8090-8097.

Research output: Contribution to journalArticle

Atochina-Vasserman, Elena N. ; Beers, Michael F. ; Kadire, Helchem ; Tomer, Yaniv ; Inch, Adam ; Scott, Pamela ; Guo, Chang J. ; Gow, Andrew J. / Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice. In: Journal of Immunology. 2007 ; Vol. 179, No. 12. pp. 8090-8097.
@article{229d9e05b2664d86b49b209c1e05e04a,
title = "Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice",
abstract = "Surfactant protein D (SP-D)-deficient (SP-D-/-) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1{\%} of saline-treated 10-wk-old SP-D-/- littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-γ) seen in bronchoalveolar lavage (BAL) of SP-D-/- mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3{\%} of saline-treated SP-D-/- mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D-/- mice as shown by decreases in total BAL cell count (63 ± 6{\%} of SP-D-/- control), macrophage size (>25 μm) within the BAL (62 ± 10{\%} of SP-D-/- control), and a percentage of BAL macrophages producing oxidants (76 ± 9{\%} of SP-D-/- control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.",
author = "Atochina-Vasserman, {Elena N.} and Beers, {Michael F.} and Helchem Kadire and Yaniv Tomer and Adam Inch and Pamela Scott and Guo, {Chang J.} and Gow, {Andrew J.}",
year = "2007",
month = "12",
day = "15",
language = "English",
volume = "179",
pages = "8090--8097",
journal = "Journal of Immunology",
issn = "0022-1767",
publisher = "American Association of Immunologists",
number = "12",

}

TY - JOUR

T1 - Selective inhibition of inducible NO synthase activity in vivo reverses inflammatory abnormalities in surfactant protein D-deficient mice

AU - Atochina-Vasserman, Elena N.

AU - Beers, Michael F.

AU - Kadire, Helchem

AU - Tomer, Yaniv

AU - Inch, Adam

AU - Scott, Pamela

AU - Guo, Chang J.

AU - Gow, Andrew J.

PY - 2007/12/15

Y1 - 2007/12/15

N2 - Surfactant protein D (SP-D)-deficient (SP-D-/-) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1% of saline-treated 10-wk-old SP-D-/- littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-γ) seen in bronchoalveolar lavage (BAL) of SP-D-/- mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3% of saline-treated SP-D-/- mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D-/- mice as shown by decreases in total BAL cell count (63 ± 6% of SP-D-/- control), macrophage size (>25 μm) within the BAL (62 ± 10% of SP-D-/- control), and a percentage of BAL macrophages producing oxidants (76 ± 9% of SP-D-/- control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.

AB - Surfactant protein D (SP-D)-deficient (SP-D-/-) mice exhibit early development of emphysema. Previously we have shown that SP-D deficiency results in increased production and activity of inducible NO synthase (iNOS). In this study, we examined whether treatment with the iNOS inhibitor 1400W could inhibit the inflammatory phenotype. Mice were treated with 1400W systemically for 7 wk from 3 wk of age. Treatment reduced total lung NO synthase activity to 14.7 ± 6.1% of saline-treated 10-wk-old SP-D-/- littermates. Long-term administration of 1400W reduced lung inflammation and cellular infiltration; and significantly attenuated the increased levels of matrix metalloproteinases 2 and 9, chemokines (KC, TARC), and cytokines (IFN-γ) seen in bronchoalveolar lavage (BAL) of SP-D-/- mice. Abrogation of these levels was associated with decreasing BAL chemotactic activity for RAW cells. Two weeks of treatment with 1400W reduced total lung NO synthase (NOS) activity to 12.7 ± 6.3% of saline-treated SP-D-/- mice. Short-term iNOS inhibition resulted in attenuation of pulmonary inflammation within SP-D-/- mice as shown by decreases in total BAL cell count (63 ± 6% of SP-D-/- control), macrophage size (>25 μm) within the BAL (62 ± 10% of SP-D-/- control), and a percentage of BAL macrophages producing oxidants (76 ± 9% of SP-D-/- control). These studies showed that s.c. delivery of 1400W can be achieved in vivo and can attenuate the inflammatory processes within SP-D deficiency. Our results represent the first report linking defects in the innate immune system in the lung with alterations in NO homeostasis.

UR - http://www.scopus.com/inward/record.url?scp=40049099026&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=40049099026&partnerID=8YFLogxK

M3 - Article

VL - 179

SP - 8090

EP - 8097

JO - Journal of Immunology

JF - Journal of Immunology

SN - 0022-1767

IS - 12

ER -