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, in large part, by disrupting essential alveolar macrophage functions. Emerging evidence suggests that these functional deficits could be due 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 is also important for regulating surfactant homeostasis in the lung. For example, mice with targeted deletion of the gene for GM-CSF accumulate large amounts of phospholipids in their lung. Moreover, decreased GM-CSF signaling in humans has been mechanistically 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 respiratory infections. Consistent with parallel mechanisms in the PAP and alcoholic lung, we recently reported that levels of intrapulmonary lipids, albeit triglycerides and free fatty acids, were markedly 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 was capable of inducing 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 propose a mechanism by which lipid accumulation itself can contribute to altering alveolar macrophage behaviors and propose how targeting this mechanism could potentially reduce the susceptibility to pulmonary infections in alcoholics.

Levels of Clara cell secretory protein and surfactant protein A in municipal solid waste management workers in Ibadan, Southwest Nigeria

“…Alcohol and tobacco are known to interfere with the production of surfactants and as such persons who take or use these substances were excluded from the study. Similarly, individuals with conditions like diabetes, asthma, and obesity, in which release of surfactants has been linked to their pathogenesis and/or pathophysiology, were also not included in the study (Alkwai et al, 2020; Slovinsky et al, 2019; Viklund et al, 2021). Control subjects were also selected by purposive sampling, comprising apparently healthy senior staff members of the State Hospital at Ring Road, Ibadan, based on the set inclusion and exclusion criteria.…”

Role of GM-CSF in lung balance and disease

“…Chronic alcohol exposure decreases the lung levels of Nrf2, a major transcription factor that regulates the expression of many antioxidant genes in cells. Nrf2 regulates the expression of PU.1 in the lungs, suggesting that the decrease in antioxidant response function may be related to the decrease in GM-CSF activity in alcoholic lungs and lung immunodeficiency (76). Chronic alcohol exposure can also lead to reduced levels of alveolar epithelial GM-CSF receptors, that alcohol can extensively disrupt GM-CSF signaling in the lungs (78), and that the absence of GM-CSF signaling disrupts the epithelial barrier function in the distal lung epithelium.…”

“…AMs in alcoholics are defective in cell adhesion, cytokine production, and phagocytosis ( 75 , 76 ). Alcohol may affect lung immune function by affecting GM-CSF signaling ( 77 , 78 ).…”

“…Chronic alcohol exposure decreases the lung levels of Nrf2, a major transcription factor that regulates the expression of many antioxidant genes in cells. Nrf2 regulates the expression of PU.1 in the lungs, suggesting that the decrease in antioxidant response function may be related to the decrease in GM-CSF activity in alcoholic lungs and lung immunodeficiency ( 76 ).…”

“…Chronic alcohol exposure can also lead to reduced levels of alveolar epithelial GM-CSF receptors, suggesting that alcohol can extensively disrupt GM-CSF signaling in the lungs ( 78 ), and that the absence of GM-CSF signaling disrupts the epithelial barrier function in the distal lung epithelium. This could explain why alcoholics are more likely to develop acute respiratory distress syndrome (ARDS) based on increased alveolar wall permeability ( 76 , 80 , 81 ). Therefore, the lack of GM-CSF signaling plays a key role in pulmonary dysfunction in patients with alcoholism, and GM-CSF replacement therapy has been used to improve lung complications in patients with alcoholism ( 82 ).…”