Published online before print July 15, 2009

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(Journal of Leukocyte Biology. 2009;86:913-922.)
© 2009 Society for Leukocyte Biology

Up-regulation of alveolar macrophage matrix metalloproteinases in HIV1⁺ smokers with early emphysema

Robert J. Kaner^*,, Francisco Santiago and Ronald G. Crystal^*,,1

^* Division of Pulmonary and Critical Care Medicine and
Department of Genetic Medicine, Weill Cornell Medical College, New York, New York, USA

1. Correspondence: Department of Genetic Medicine, Weill Cornell Medical College, 1300 York Avenue, Box 96, New York, NY 10065, USA. E-mail: geneticmedicine{at}med.cornell.edu

ABSTRACT

HIV1⁺ smokers develop emphysema at an earlier age and with a higher incidence than HIV1^– smokers. Since human alveolar macrophages (AMs) are capable of producing proteases that degrade extracellular matrix components, we hypothesized that up-regulation of AM matrix metalloproteinases may be associated with the emphysema of HIV1⁺ smokers. Microarray analysis was used to screen which matrix metalloproteinases (MMPs) genes were expressed by AM of HIV1⁺ smokers with early emphysema. For each of the MMP genes expressed (MMP-1, -2, -7, -9, -10, -12 and -14), TaqMan PCR was used to quantify the relative expression in AM from four groups of individuals: HIV1^– healthy nonsmokers, HIV1^– healthy smokers, HIV1^– smokers with early emphysema, and HIV1⁺ smokers with early emphysema. While AM gene expression of MMPs was higher in HIV1^– individuals with emphysema in comparison with HIV1^– healthy smokers, for the majority of the MMPs (-1, -7, -9, and -12), AM expression from HIV1⁺ smokers with early emphysema was significantly higher than in HIV1^– smokers with early emphysema. HIV1⁺ individuals with early emphysema also had higher levels of epithelial lining fluid (ELF) MMPs (-2, -7, -9, and -12) than the 3 HIV1^– groups. ELF MMP (-2,-7,-9, and -12) levels were similar in HIV1⁺ nonsmokers compared with HIV1^– nonsmokers. Interestingly, the active forms of MMP-2, -9, and -12 were exclusively detected in ELF from HIV1⁺ individuals with early emphysema. Since the activities of the up-regulated AM MMPs include collagenases, gelatinases, matrilysins, and elastase, these data suggest that up-regulated AM MMP genes and activation of MMP proteins may contribute to the emphysema of HIV1⁺ individuals who smoke.

Key Words: lung • protease • lung disease • pathogenesis • human