Background/Purpose: Most Chronic Obstructive Pulmonary Disease (COPD) cases result from amplification of normal inflammatory responses due to noxious stimuli like cigarette smoke. Yet, the mechanism by which COPD lungs continue to deteriorate despite smoking cessation is not well understood. Here, we explore an auto-inflammatory component of COPD via the study of NKG2D (natural-killer group 2, member D) ligands and a cytokine shown to directly activate natural killer (NK) cells, IL-27. Research in COPD murine models has demonstrated high NKG2D receptor expression on pulmonary NK cells and NK hyper-responsiveness as a result. NK cell activation then leads to destruction of damaged or stressed pulmonary cells and further deteriorates lung parenchyma. We hypothesize that COPD patient serum will show increased expression of soluble NKG2D ligands and IL-27 correlating to a progressive decline in lung function in active but also former smokers.

Methods: COPD patient serum samples were collected from nine hospitals in Spain (1/2004-3/2006). NKG2D ligand and IL27 expression in COPD patients and healthy subjects was compared via sandwich ELISA method and p-values were determined using independent t-test calculations.

Results: When looking at patient groups defined by smoking status, former and active smokers had increased expression on NKG2D ligands (ULBP2, ULBP3 and MICA) and IL-27 compared to controls. ULBP2 expression comparison showed the following: never smokers = 1.03 pg/mL (N=27, SD ±5.35 pg/mL) compared to active smokers= 18.30 pg/mL (N=22, SD ±71.90 pg/mL, p<0.05) and former smokers 25.28 pm/mL (N=29, SD ±119.00, p<0.05). ULBP3 expression: never smokers = 25.92 pg/mL (N=27, SD ±72.92 pg/mL) compared to active smokers= 77.50 pg/mL (N=23, SD ±267.55 pg/mL, p<0.05) and former smokers 79.12 pg/mL (N=29, SD ±362.06, p<0.05). MICA expression: never smokers = 290.28 pg/mL (N= 100, SD ±1737.34 pg/mL) compared to active smokers= 887.06 pg/mL (N=162, SD ±3405.86 pg/mL, p<0.05) and former smokers 737.27 pg/mL (N=159, SD ±3767.09, p<0.05).  IL-27 expression: never smokers = 217.50 pg/mL (N=27, SD ±613.41 pg/mL) compared to active smokers= 432.45 pg/mL (N=23, ±SD 745.27 pg/mL, p<0.05) and former smokers 367.26 pg/mL (N=29, SD ±1110.82, p<0.05).

Conclusion: Our data shows higher mean quantities of soluble NKG2D ligands and IL-27 in COPD patients compared to healthy controls. Within the COPD patients, the ligand and cytokine expression seen in former smokers was comparable to that of active smokers and significantly elevated compared to healthy controls. These findings give us further insight to diagnosis and management of COPD. Diagnostically, ligand levels could help us differentiate COPD subtypes or ligand expression can correlate with varied disease progression. Future plans involve finding a direct correlation between the expression of NKG2D receptors on lung parenchyma and soluble NKG2D ligands in the serum. We can then utilize this insight of the COPD pathophysiology to evaluate if novel treatments for COPD, like biologic agents, could be used to curtail the process by which COPD lungs continue to deteriorate despite smoking cessation.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/investigating-an-auto-inflammatory-component-of-copd-that-contributes-to-progressive-decline-in-lung-function-despite-smoking-cessation/