Human Alveolar Macrophage Growth Factor for Fibroblasts

Abstract

A B S T R A C T The number of fibroblasts composing the alveolar structures is controlled within narrow limits by a strictly modulated rate of fibroblast replication. One possible source of growth-modulating signals for alveolar fibroblasts is the alveolar macrophage, a member of the mononuclear phagocyte family of cells, which collectively are known to be important sources of growth factors for a variety of target cells. To evaluate the role of alveolar macrophages in the control of alveolar fibroblast replication, macrophages from normal individuals obtained by bronchoalveolar lavage were maintained in suspension culture with and without added stimuli, and supernates were evaluated for fibroblast growth-promoting effect. Supernates from unstimulated macrophages contained no growth factor activity. In marked contrast, supernates from macrophages stimulated with particulates and immune complexes contained a growth factor that caused a significant increase in fibroblast replication rate. Maximum growth factor activity was observed 3-4 h after macrophage stimulation, at a concentration of 1-2 X 106 macrophages/ml. The alveolar macrophagederived growth factor eluted from DEAE-cellulose at 0.27 M NaCI at neutral pH had an apparent molecular weight of 18,000, and appeared to be distinct from other characterized growth factors. The alveolar macrophage-derived growth factor stimulated lung fibroblast DNA synthesis within 12 h, with cell division apparent within 48 h. In serum-free culture, the alveolar macrophage-derived growth factor by itself did not promote fibroblast replication, but rather acted as a progression factor causing a synergistic increase in fibroblast replication rate in the presence of competence factors such as fibroblast growth factor or platelet-derived growth factor. These studies suggest that

Pulmonary immune responses induced in BALB/c mice by Paracoccidioides brasiliensis conidia

“…It may also be the result of cryptogenic processes [142][143][144]. In these diseases, fibrosis shares common characteristics, including fibroblast proliferation and extracellular matrix deposition [145][146][147]. Lung fibrosis often follows a series of chronic granulomatous processes.…”

Alveolar macrophages release an insulin-like growth factor I-type molecule.

“…These cells are also capable of producing a "progression" factor. In 1982, Bitterman and colleagues (26) described a polypeptide with "progression" activity released from activated alveolar macrophages. This mediator, termed "alveolar macrophage-derived growth factor" (or AMDGF) had no "competence" activity, but in serum-free conditions was capable of stimulating PDGF or fibronectin-primed fibroblasts to move through GI and synthesize DNA within 8 h (25).…”

“…Furthermore, in fibrotic lung disorders such as IPF and asbestosis, AMDGF was spontaneously released, but was not detectable in supernatants of normal resting alveolar macrophages (27,28). At the time of its discovery, evaluation of AMDGF suggested it was different from all other known growth factors (26). Specifically, in regards to the "progression" class of fibroblast growth factors, its apparent molecular mass insured it was not insulin, insulinlike growth factor-I (IGF-I, "somatomedin C") or insulin-like growth factor-II (IGF-II) (29).…”

“…The progression-type growth factor activity released by the activated alveolar macrophages was quantified using a complementation assay as previously described in detail for AMDGF (26). After incubation of column fractions with noncycling fibroblasts, cells were detached with 0.25% trypsin and counted in a cell counter (Coulter Electronics, Inc., Hialeah, FL).…”

Minerals, Fibrosis, and the Lung

“…Increase in the fibroblast population may then contribute to connective tissue formation. Enhanced growth offibroblasts and collagen production were promoted by blood monocytes via mediators (227) or by a factor released from human alveolar macrophages after stimulation by nonmineral particles (228). However, this macrophage-derived growth factor (MDGF) was unable by itselfto stimulate fibroblast replication, for which initiating factors provided by fibroblasts or platelets were required to establish competence.…”