Reduced airway levels of fatty-acid binding protein 4 in COPD: relationship with airway infection and disease severity

Abstract

Background: For still unclear reasons, chronic airway infection often occurs in patients with Chronic Obstructive Pulmonary Disease (COPD), particularly in those with more severe airflow limitation. Fatty-acid binding protein 4 (FABP4) is an adipokine involved in the innate immune response against infection produced by alveolar macrophages (Mɸ). We hypothesized that airway levels of FABP4 may be altered in COPD patients with chronic airway infection. Methods: In this prospective and controlled study we: (1) compared airway FABP4 levels (ELISA) in induced sputum, bronchoalveolar lavage fluid (BALF) and plasma samples in 52 clinically stable COPD patients (65.2 ± 7.9 years, FEV 1 59 ± 16% predicted) and 29 healthy volunteers (55.0 ± 12.3 years, FEV 1 97 ± 16% predicted); (2) explored their relationship with the presence of bacterial airway infection, defined by the presence of potentially pathogenic bacteria (PPB) at ≥10 3 colony-forming units/ml in BALF; (3) investigated their relationship with the quantity and proportion of Mɸ in BALF (flow cytometry); and, (4) studied their relationship with the severity of airflow limitation (FEV 1 ), GOLD grade and level of symptoms (CAT questionnaire). Results: We found that: (1) airway levels of FABP4 (but not plasma ones) were reduced in COPD patients vs. controls [219.2 (96.0-319.6) vs. 273.4 (203.1-426.7) (pg/ml)/protein, p = 0.03 in BALF]; (2) COPD patients with airway infection had lower sputum FABP4 levels [0.73 (0.35-15.3) vs. 15.6 (2.0-29.4) ng/ml, p = 0.02]; (3) in COPD patients, the number and proportion of Mɸ were positively related with FABP4 levels in BALF; (4) BALF and sputum FABP4 levels were positively related with FEV 1 , negatively with the CAT score, and lowest in GOLD grade D patients. Conclusions: Airway FABP4 levels are reduced in COPD patients, especially in those with airway infection and more severe disease. The relationship observed between Mɸ and airway FABP4 levels supports a role for FABP4 in the pathogenesis of airway infection and disease severity in COPD.

Innate immunity plays a key role in controlling viral load in COVID-19: mechanistic insights from a whole-body infection dynamics model

“…Lack of IFNs can lead to excessive viral production 33 and cause life-threating COVID-19 in patients deficient in functional IFNs due to, for example, the occurrence of loss-of-function mutations in genes governing IFN-mediated immunity 32 or auto-antibodies against IFNs 31 . Further, FABP4+ alveolar macrophages were observed to be largely absent in patients with severe COVID-19, but were a predominant macrophage in patients with mild disease 50 , indicating the major role of FABP4+ alveolar macrophages in controlling infection as also shown previously for patients with chronic obstructive pulmonary disease (COPD) 51 . We assume a constant supply of macrophages in the lungs and MPS in our model, but a deleterious effect of infection on these immune cells cannot be ruled out, and further experimental evidence is necessary to model the cell population kinetics appropriately 52 .…”

Innate Immunity Plays a Key Role in Controlling Viral Load in COVID-19: Mechanistic Insights from a Whole-Body Infection Dynamics Model

“…Lack of IFNs can lead to excessive viral production and cause life-threating COVID-19 in patients deficient in functional IFNs due to, for example, the occurrence of loss-of-function mutations in genes governing IFN-mediated immunity or autoantibodies against IFNs . Further, FABP4+ alveolar macrophages were observed to be largely absent in patients with severe COVID-19 but were the predominant macrophage in patients with mild disease, indicating the major role of FABP4+ alveolar macrophages in controlling infection as also shown previously for patients with chronic obstructive pulmonary disease (COPD) . We assume a constant supply of macrophages in the lungs and MPS in our model, but a deleterious effect of infection on these immune cells cannot be ruled out, and further experimental evidence is necessary to model the macrophage population kinetics more appropriately .…”

“…32 Further, FABP4+ alveolar macrophages were observed to be largely absent in patients with severe COVID-19 but were the predominant macrophage in patients with mild disease, 57 indicating the major role of FABP4+ alveolar macrophages in controlling infection as also shown previously for patients with chronic obstructive pulmonary disease (COPD). 58 We assume a constant supply of macrophages in the lungs and MPS in our model, but a deleterious effect of infection on these immune cells cannot be ruled out, and further experimental evidence is necessary to model the macrophage population kinetics more appropriately. 59 Further, the model reveals that the effect of adaptive immunity (antibodies and CD8* cells) is not significant in controlling infection, but it does not necessarily rule out the therapeutic potential of exogenously administered antibodies or novel cell-based therapies (e.g., T cell therapy).…”

Cigarette smoke extract-mediated FABP4 upregulation suppresses viability and induces apoptosis, inflammation and oxidative stress of bronchial epithelial cells by activating p38 MAPK/MK2 signaling pathway

“…FABP4 levels also positively correlated with adiponectin and tumor necrosis factor α in COPD patients [ 13 ]. On the contrary, another study has revealed that airway FABP4 levels are reduced in COPD patients [ 14 ]. Although the above studies reported the controversial effect of FABP4 on COPD, they all suggested the important role of FABP4 in COPD pathogenesis.…”