The involvement of GM-CSF deficiencies in parallel pathways of pulmonary alveolar proteinosis and the alcoholic lung

Abstract

Chronic alcohol consumption renders the lung more susceptible to infections by disrupting essential alveolar macrophage functions. Emerging evidence suggests that these functional deficits are due, in part, to a suppression of GM-CSF signaling, which is believed to compromise monocyte growth and maturation in the lung. However, in addition to controlling monocyte behaviors, GM-CSF also regulates surfactant homeostasis. For example, mice with targeted deletion of the gene for GM-CSF accumulate large amounts of surfactant phospholipids in their lungs. Moreover, decreased GM-CSF signaling in humans has been linked to the development of pulmonary alveolar proteinosis (PAP), a rare disorder in which surfactant lipids and proteins accumulate in alveolar macrophages and the lung exhibits enhanced susceptibility to infection. Consistent with parallel mechanisms in the PAP and alcoholic lung, we have recently reported that levels of intrapulmonary lipids, specifically triglycerides and free fatty acids, are increased in BAL fluid, whole lung digests and alveolar macrophages of chronically alcohol exposed rats. Additionally, we showed that uptake of saturated fatty acids alone could induce phenotypic and functional changes in alveolar macrophages that mimicked those in the alcohol-exposed rat and human lung. Herein, we discuss the role of GM-CSF in surfactant homeostasis and highlight the evidence that links decreased GM-CSF signaling to alveolar macrophage dysfunction in both the PAP and alcohol-exposed lung. Moreover, we discuss how lipid accumulation itself might contribute to altering alveolar macrophage function and propose how targeting these mechanisms could be employed for reducing the susceptibility to pulmonary infections in alcoholics.

Keywords: Acute respiratory distress syndrome; Alcohol use disorder; GM-CSF; Metabolism; Pneumonia; Pulmonary surfactant.

Figure 1:

Comparison of alveolar pathologies between pulmonary alveolar proteinosis (PAP) and chronically ethanol exposed lung. A hallmark of both conditions is the lipid-laden morphology of macrophages caused by the accumulation of lipids (yellow circles) in the cytosol, and the development of immunoregulatory dysfunction. Acquired forms of PAP develop because of autoantibodies preventing GM-CSF (green triangles) from binding to receptors in the plasma membranes of alveolar macrophages and type II alveolar epithelial cells. By contrast, levels of GM-CSF receptors (red color shapes) are reduced in the alveoli in response to chronic alcohol exposure. Lipid synthesis is also increased in alveolar epithelial type II cells in response to alcohol. In both the PAP and chronic alcohol exposed lung, decreased GM-CSF signaling leads to reduced PU.1 levels in the nucleus (charcoal gray oval) of AMs. Increased ROS levels have been observed in the mitochondria of ethanol metabolizing cells, which may also contribute to alterations in lipid homeostasis in the lung after chronic ethanol consumption.

Figure 2:

Potential therapeutic approaches to blocking lipid-laden macrophage formation and restoring alveolar macrophage function in alcoholics. Exogenous GM-CSF replacement therapy (dark green) could be used to enhance GM-CSF signaling and upregulate the expression of lipid transporter proteins. This could also be achieved by augmenting the activity of molecules downstream of the GM-CSF receptor, like PPARγ (thiazolidinedione). Alternatively, the effects of fatty acids (yellow curved line) on macrophage behavior could be attenuated by blocking: 1) the uptake of fatty acids from scavenger receptors (CD36); 2) the binding of fatty acids to fatty acid binding proteins (FABP); and 3) the entry of fatty acids into mitochondria (CPT1 inhibitor etomoxir). Lastly, lipid-laden macrophage formation could be reduced by suppressing lipid synthesis in type II alveolar epithelial cells with drugs that block alcohol metabolism (bottom of figure).