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*Compound via MeSH
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*CYCLOPHOSPHAMIDE
*L-TYROSINE
*NITRIC OXIDE

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Infection and Immunity, October 2001, p. 6401-6410, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6401-6410.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Cyclophosphamide Decreases Nitrotyrosine Formation and Inhibits Nitric Oxide Production by Alveolar Macrophages in Mycoplasmosis

Judy M. Hickman-Davis,1 J. Russell Lindsey,2 and Sadis Matalon1,2,3,*

Departments of Anesthesiology,1 Genomics and Pathobiology,2 and Physiology and Biophysics,3 Schools of Medicine and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama 35294

Received 22 February 2001/Returned for modification 9 May 2001/Accepted 11 June 2001

We previously reported that congenic C57BL/6 inducible nitric oxide synthase-/- (iNOS-/-) mice infected with Mycoplasma pulmonis developed higher bacterial numbers and lung lesion scores than C57BL/6 iNOS+/+ controls but had similar lung nitrotyrosine levels. The present studies investigated the role of inflammatory cells in nitrotyrosine formation during mycoplasmal infection. iNOS+/+ and iNOS-/- mice were injected with cyclophosphamide (CYP) and inoculated with 107 CFU of M. pulmonis. CYP pretreatment of M. pulmonis-infected iNOS+/+ and iNOS-/- mice reduced polymorphonuclear cells (PMNs) within bronchoalveolar lavages (BALs) by 88 and 72%, respectively, and whole-lung myeloperoxidase levels by 80 and 78%, respectively, at 72 h postinfection but did not alter the number of alveolar macrophages (AMs) in BALs. CYP treatment also significantly decreased nitrate and nitrite (NOx) levels in BALs and plasma of infected iNOS+/+ mice, whereas neither CYP nor mycoplasmal infection altered NOx in iNOS-/- mice. CYP reduced lung nitrotyrosine levels in both iNOS+/+ and iNOS-/- mice to uninfected-control levels as shown by immunohistochemical staining and enzyme-linked immunosorbent assay and inhibited mycoplasmal killing by iNOS+/+ mice in vivo. CYP inhibited the production of gamma interferon-inducible NOx by iNOS+/+ AMs in vitro but did not alter the number of iNOS-positive AMs, as detected by immunocytochemistry. In addition, AMs from CYP-treated iNOS+/+ mice had significantly decreased ability to kill mycoplasmas in vitro. These results demonstrate that reactive species generated by inflammatory cells as well as PMN myeloperoxidase are important contributors to nitrotyrosine formation during mycoplasmal infection and that treatment with CYP decreases NO· production by AMs and inhibits mycoplasmal killing.

* Corresponding author. Mailing address: Department of Anesthesiology, University of Alabama at Birmingham, 619 South 19th St., THT 940, Birmingham, AL 35294. Phone: (205) 934-4231. Fax: (205) 934-7437. E-mail: Sadis.Matalon{at}ccc.uab.edu.

Infection and Immunity, October 2001, p. 6401-6410, Vol. 69, No. 10
0019-9567/01/$04.00+0   DOI: 10.1128/IAI.69.10.6401-6410.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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