Alveolar macrophage deficiency in osteopetrotic mice deficient in macrophage colony-stimulating factor is spontaneously corrected with age and associated with matrix metalloproteinase expression and emphysema

Macrophage colony-stimulating factor (M-CSF) is one of several hematologic growth factors capable of regulating the survival, proliferation, and diffe rentiation of macrophages, but its role in modulation of the accumulation a nd function of alveolar macrophages (AMs) in vivo is not well defined. Oste opetrotic (Op/Op) mice have no detectable M-CSF and show variable tissue-sp ecific reductions in macrophage numbers. It was hypothesized that AMs would be decreased in number and have altered function in Op/Op mice because of the absence of M-CSF Lung macrophages identified by Mac-3 staining in lung sections were decreased in number in 20-day-old Op/Op mice (P < .001) but n ot Op/Op mice older than 4 months (P = .68) compared with findings in age-m atched littermate controls. The numbers of AMs recovered by bronchoalveolar lavage (BAL) were also reduced in young but not adult Op/Op mice compared with controls. Expression of interleukin-3 (IL-3) was increased in the lung s of Op/Op mice compared with controls as determined by quantification of I L-3 cytokine levels (P = .04), bioactivity (P = .02), and messenger RNA tra nscript levels. AMs of Op/Op mice spontaneously released higher levels of m atrix metalloproteinases (MMPs) than AMs of controls as determined by immun ohistochemical staining of AMs and zymographic assessment of BAL fluid and AM lysates. Consistent with an increased release of MMP, Op/Op mice had abn ormal elastin deposition and spontaneously developed emphysema in the absen ce of molecular or cellular evidence of lung inflammation. These data show that the AM deficiency observed in young Op/Op mice is spontaneously correc ted with age and is associated with increased lung levels of IL-3, spontane ous MMP expression by AMs, and destruction of lung tissue. (C) 2001 by The American Society of Hematology.