Increased Pulmonary GM-CSF Causes Alveolar Macrophage Accumulation. Mechanistic Implications for Desquamative Interstitial Pneumonitis.

Abstract

Desquamative interstitial pneumonia (DIP) is a rare, smoking-related, diffuse parenchymal lung disease characterized by marked accumulation of alveolar macrophages (AMs) and emphysema, without extensive fibrosis or neutrophilic inflammation. Because smoking increases expression of pulmonary GM-CSF (granulocyte/macrophage-colony stimulating factor) and GM-CSF stimulates proliferation and activation of AMs, we hypothesized that chronic exposure of mice to increased pulmonary GM-CSF may recapitulate DIP. Wild-type (WT) mice were subjected to inhaled cigarette smoke exposure for 16 months, and AM numbers and pulmonary GM-CSF mRNA levels were measured. After demonstrating that smoke inhalation increased pulmonary GM-CSF in WT mice, transgenic mice overexpressing pulmonary GM-CSF (SPC-GM-CSF+/+) were used to determine the effects of chronic exposure to increased pulmonary GM-CSF (without smoke inhalation) on accumulation and activation of AMs, pulmonary matrix metalloproteinase (MMP) expression and activity, lung histopathology, development of polycythemia, and survival. In WT mice, smoke exposure markedly increased pulmonary GM-CSF and AM accumulation. In unexposed SPC-GM-CSF+/+ mice, AMs were spontaneously activated as shown by phosphorylation of STAT5 (signal inducer and activator of transcription 5) and accumulated progressively with involvement of 84% (interquartile range, 55-90%) of the lung parenchyma by 10 months of age. Histopathologic features also included scattered multinucleated giant cells, alveolar epithelial cell hyperplasia, and mild alveolar wall thickening. SPC-GM-CSF+/+ mice had increased pulmonary MMP-9 and MMP-12 levels, spontaneously developed emphysema and secondary polycythemia, and had increased mortality compared with WT mice. Results show cigarette smoke increased pulmonary GM-CSF and AM proliferation, and chronically increased pulmonary GM-CSF recapitulated the cardinal features of DIP, including AM accumulation, emphysema, secondary polycythemia, and increased mortality in mice. These observations suggest pulmonary GM-CSF may be involved in the pathogenesis of DIP.

• Authors: Takuji Suzuki, Cormac McCarthy, Brenna C Carey, Michael Borchers, David Beck, Kathryn A Wikenheiser-Brokamp, Dianna Black, Claudia Chalk, Bruce C Trapnell
• Journal: American journal of respiratory cell and molecular biology (Am J Respir Cell Mol Biol) Vol. 62 Issue 1 Pg. 87-94 (01 2020) ISSN: 1535-4989 [Electronic] United States
• PMID: 31310562 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• STAT5 Transcription Factor
• Granulocyte-Macrophage Colony-Stimulating Factor
• Matrix Metalloproteinase 9
• Matrix Metalloproteinase 12

Topics

• Animals
• Emphysema (metabolism)
• Epithelial Cells (metabolism)
• Genetic Diseases, Inborn (metabolism)
• Granulocyte-Macrophage Colony-Stimulating Factor (metabolism)
• Hyperplasia (metabolism)
• Lung (metabolism)
• Lung Diseases, Interstitial (metabolism)
• Macrophages, Alveolar (metabolism)
• Matrix Metalloproteinase 12 (metabolism)
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Polycythemia (metabolism)
• Pulmonary Alveoli (metabolism)
• STAT5 Transcription Factor (metabolism)
• Smoking (metabolism)