Departments of 1 Medicine and 2 Cell Biology, Duke University Medical Center, Durham, North Carolina 27710
PULMONARY ALVEOLAR PROTEINOSIS (PAP) is a rare but
potentially deadly disease characterized by an accumulation of
surfactant in the alveolar air spaces, which ultimately results in
impaired gas exchange (5). Although a few cases of this
disease can be attributed to exposure to dusts such as silica, the
etiology of most cases is not known.
Insights, some quite surprising, into the possible mechanism of
accumulation of surfactant in PAP have come from a variety of mouse
models. The first clue in the mystery was provided by the
granulocyte-macrophage colony-stimulating factory (GM-CSF) knockout mouse (3, 12). Initially characterized as a
factor from lung-conditioned medium that stimulated the proliferation and differentiation of immune cells from hematopoietic progenitors, GM-CSF has been identified as a 23-kDa glycoprotein that also modulates
the function of mature hematopoietic cells. Thus it seemed logical to
speculate that depletion of GM-CSF would affect hematopoiesis. However,
the GM-CSF-deficient mice had a normal number of peripheral blood
cells, bone marrow progenitors, and populations of tissue hematopoietic
cells. Unexpectedly, the mice all exhibited excessive intra-alveolar
accumulation of surfactant lipids and proteins in the air spaces.
Additional evidence for involvement of this cytokine in the development
of PAP in mice was provided by further studies (9, 10) in
which ablation of the How could this glycoprotein initially thought to be only an essential
maturation factor for hematopoietic cells alter surfactant metabolism?
A previous study (4) with GM-CSF-deficient mice provided
evidence that the biosynthetic pathways for surfactant production were
relatively normal, suggesting that surfactant catabolism rather than
synthesis was altered (4). Both the alveolar type II cell
and the alveolar macrophage participate in surfactant catabolism. The
paper by Yoshida et al. (15) published in this
issue provides clear evidence that the degradative functions of
alveolar macrophages are impaired in GM-CSF-deficient mice. Using
isolated macrophages from wild-type, GM-CSF-deficient, and transgene-corrected GM-CSF mice, the authors demonstrated that GM-CSF
deficiency has a profound effect on the ability of macrophages to
degrade surfactant lipids and surfactant protein (SP) A. Surprisingly, binding of lipid and SP-A to the cells was not altered or was even
enhanced, suggesting that it is the degradative pathway that is
specifically impaired. Expression of GM-CSF in the lung, driven by the
SP-C promoter, corrected the catabolic defect in alveolar macrophages
but not in peritoneal macrophages. These studies suggest that
GM-CSF is acting as a differentiation or maturation factor rather than
as a direct activator of macrophage function and that local production
of GM-CSF is required to correct the catabolic defect.
Based on these studies, one might expect that PAP in humans may be due
to GM-CSF deficiency and that treatment with GM-CSF may provide a
therapy. There are case reports of clinical responses of patients with
PAP to administration of recombinant human GM-CSF (7, 11).
The disease, however, has a 30% spontaneous remission rate,
confounding interpretation of results from small uncontrolled clinical
studies. Furthermore, unfolding evidence demonstrates that the scenario
is not as simple as the mouse models would lead one to believe. This is
not surprising because PAP is likely a common phenotypic response of
the lung to a number of biochemical or molecular abnormalities. In some
patients, defective expression of GM-CSF/interleukin (IL)-3/IL-5
receptor common Although the paper by Yoshida et al. (15) provides
important new information about the mechanism by which a deficiency of GM-CSF induces alterations in surfactant metabolism, many unanswered questions remain about this complex disease. Additional studies with
both mice and humans that lead to a further understanding of
macrophage-degradative pathways of surfactant and how these pathways might be upregulated as well as to an understanding of how
GM-CSF affects macrophage differentiation could provide important clues
about the etiology and treatment of PAP.
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REFERENCES
-subunit of the mouse GM-CSF receptor (which
is shared by interleukin-3 and interleukin-5 receptors) resulted in the PAP phenotype.
-chain has been identified (1).
Defective hematopoietic response to exogenous administration of GM-CSF
in PAP patients also suggests that an abnormal GM-CSF receptor could be
pathogenic in the disease in some cases (7, 11). It has
also been demonstrated that some patients with PAP have anti-GM-CSF
antibodies, which may neutralize its activity (6, 13).
However, the direct relevance of antibodies to GM-CSF in the
pathogenesis of the disease has yet to be demonstrated. For example,
some patients with PAP have measurable levels of free GM-CSF in both
lavage fluid and serum (2). Furthermore, as Kitamura et
al. (6) pointed out, antibody to GM-CSF is found commonly
in IgG preparations and in patients receiving GM-CSF therapeutically,
yet there are no reports of PAP in these patients. It is also possible
that only small amounts of GM-CSF are required for bioactivity because,
like other cytokines, GM-CSF receptor density is very low (100-300
receptors/cell), and cytokine activation of intracellular effects
through receptor binding requires only 5-10% receptor occupancy.
Other authors (14) have shown that elevation of IL-10 in
some patients with PAP may contribute to reduced GM-CSF levels. In any
case, treatment with exogenous GM-CSF would not be expected to be an
effective treatment for PAP in the scenario where antibodies are
present or receptors are defective.
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