Association of Elevated Serum GM-CSF, IFN- γ, IL-4, and TNF- α Concentration with Tobacco Smoke Induced Chronic Obstructive Pulmonary Disease in a South Indian Population

Abstract

Background: Chronic obstructive pulmonary disease (COPD) is a devastating condition with limited pharmacotherapeutic options and exceptionally high public-health burden globally as well as in India. Tobacco smoking is the primary cause for COPD among men in India. Systemic inflammation involving altered regulation of cytokines controlling the host defense mechanism is a hallmark of COPD pathogenesis. However, biomarker discovery studies are limited among Indian COPD patients.

Methods: We assessed the serum concentrations [median (25th-75th percentile) pg/ml] of interleukin (IL)-2,4,6,8,10, granulocyte macrophage colony stimulating factor (GM-CSF), interferon gamma (IFN-γ), and tumor necrosis factor alpha (TNF-α) using a multiplexed immunoassay. Our study cohort consisted of 30 tobacco smokers with COPD (TS COPD) and 20 tobacco smokers without COPD (TS CONTROL) from South India. The study population was matched for age, sex (male), and tobacco consumption (pack-years). COPD was diagnosed according to the global initiative for chronic obstructive lung disease (GOLD) criteria of persistent airflow obstruction determined by the ratio of postbronchodilator forced expiratory volume in 1 second/forced vital capacity (FEV₁/FVC) of <0.7. A validated structured questionnaire-based survey [Burden of Obstructive Lung Disease (BOLD) study] and spirometry were performed during house to house visit of the field study. Statistical analysis included nonparametric (two-tailed) Mann-Whitney U and Spearman rank test, as appropriate (significance: p<0.05).

Results: Serum GM-CSF [69.64 (46.67, 97.48); 36.78 (30.07, 53.88), p=0.014], IFN-γ [51.06 (17.00, 84.86); 11.70 (3.18, 32.81), p=0.017], IL-4 [9.09 (1.8, 19.9); 1.8 (1.8, 4.46); p=0.024], and TNF-α [20.68 (5.5, 29.26); 3.5 (3.5, 4.5); p<0.001] concentrations (pg/ml) were increased in TS COPD subjects compared to TS CONTROL. A weak correlation between lung function parameters and cytokine concentrations was detected.

Conclusion: Our pilot study reveals GM-CSF, IFN-γ, IL-4, and TNF-α as plausible COPD susceptibility biomarkers within the investigated South Indian population that needs to be validated in a larger cohort.

Figure 1

Serum concentrations of granular macrophage colony stimulating factor (GM-CSF) and corresponding correlation with lung function parameters among long-term smokers with or without chronic obstructive pulmonary disease (COPD). (a, b) GM-CSF concentrations were increased in TS COPD group compared to TS CONTROL group (p=0.014); inverse correlation of GM-CSF concentrations to (c) FEV₁/FVC and (d) FEV_1(pre) and FEV_1(post) was detected in the study cohort. Data is presented as median (25th-75th percentile); TS COPD: n=30 and TS CONTROL: n=20; ∗p<0.05 was considered as statistically significant. COPD: chronic obstructive pulmonary disease; FEV₁/FVC: forced expiratory volume 1 second /forced vital capacity; FEV_1(pre): forced expiratory volume 1 second prebronchodilator challenge; FEV_{1  (post)}: FEV₁ postbronchodilator challenge; TS COPD: tobacco smokers with COPD; TS CONTROL: tobacco smokers without COPD.

Figure 2

Serum concentrations of interferon gamma (IFN- γ ) and corresponding correlation with lung function parameters among long-term smokers with or without chronic obstructive pulmonary disease (COPD). (a, b) IFN-γ concentrations were increased in TS COPD group compared to TS CONTROL group (p=0.017); inverse correlation of IFN-γ concentrations to (c) FEV₁/FVC was detected in the study cohort. ∗p<0.05 was considered as statistically significant. Data is presented as median (25th-75th percentile); TS COPD: n=30 and TS CONTROL: n=20; ∗p<0.05 was considered as statistically significant. COPD: chronic obstructive pulmonary disease; FEV₁/FVC: forced expiratory volume 1 second postbronchodilator challenge/forced vital capacity; FEV_1(pre): forced expiratory volume 1 second prebronchodilator challenge; FEV_{1  (post)}: FEV₁ postbronchodilator challenge; TS COPD: tobacco smokers with COPD; TS CONTROL: tobacco smokers without COPD.

Figure 3

Serum concentrations of interleukin 4 (IL-4) and corresponding correlation with lung function parameters among long-term smokers with or without chronic obstructive pulmonary disease (COPD). (a, b) IL-4 concentrations were increased in TS COPD group compared to TS CONTROL group (p=0.024); inverse correlation of IL4 concentrations to (c) FEV₁/FVC and (d) FEV_1(post) was detected in the study cohort.. Data is presented as median (25th-75th percentile); TS COPD: n=30 and TS CONTROL: n=20; ∗p<0.05 was considered as statistically significant. COPD: chronic obstructive pulmonary disease; FEV_1(pre): forced expiratory volume 1 second prebronchodilator challenge; FEV_{1  (post)}: FEV₁ postbronchodilator challenge; TS COPD: tobacco smokers with COPD; TS CONTROL: tobacco smokers without COPD.

Figure 4

Serum concentrations of tumor necrosis factor alpha (TNF- α ) and corresponding correlation with lung function parameters among long-term smokers with or without chronic obstructive pulmonary disease (COPD). (a, b) TNF-α concentrations were increased in TS COPD group compared to TS CONTROL group (p<0.001); inverse correlation of TNF-α concentrations to (c) FEV₁/FVC, (d) FEV_1(pre), and (e) FEV_1(post) was detected in the study cohort. Data is presented as median (25th-75th percentile); TS COPD: n=30 and TS CONTROL: n=20; ∗p<0.05 was considered as statistically significant. COPD: chronic obstructive pulmonary disease; FEV₁/FVC: forced expiratory volume 1 second postbronchodilator challenge/forced vital capacity; FEV_1(pre): forced expiratory volume 1 second prebronchodilator challenge; FEV_{1  (post)}: FEV₁ postbronchodilator challenge; TS COPD: tobacco smokers with COPD; TS CONTROL: tobacco smokers without.