Pulmonary & Respiratory Medicine

Evidence of Elevated CXCR2 Agonists in Stable Outpatients with Cystic Fibrosis Compared with Healthy Controls

Abstract

Lipson David A, Holsclaw Douglas, Imbesi Giovanna, Ferrin Marianne, Sims Michael, Miller Sam, Tal-Singer Ruth and Hadjiliadis Denis

Introduction: Recruitment and activation of inflammatory cells contributes to the pathophysiology of Cystic Fibrosis (CF). Recruitment is initiated, in part, by engagement of the CXCR2 receptor on neutrophils and other inflammatory cells.

Materials and Methods: Levels of CXCR2 agonists (CXCL 1, 3, 5, 7, 8), and systemic biomarkers of inflammation (fibrinogen, CC-16, SP-D, IL-1β, and MMP-9) were measured in the serum of stable outpatients with cystic fibrosis compared to normal healthy age-, gender, and racially-matched non-smoking control subjects. Secondary objectives included characterization of pulmonary function assessed by spirometry, Impulse Oscillometry (IOS), R5-R15 peripheral resistance, R5 total resistance and R25 large airway resistance; frequency dependent reactance as indicators of reactive capacitance properties of the lung (X5, resonant frequency, Fres, AX) in patients with CF compared with controls. Health outcomes scores in patients with CF were assessed using the Cystic Fibrosis Questionnaire.

Population: Single center, prospective, two visit study. 48 subjects were enrolled. Forty-two subjects (28 patients with CF and 14 healthy controls matched 2:1 (age, gender, and race) were evaluable.

Results: Blood fibrinogen levels in CF patients were significantly elevated compared with controls (3.9 g/L vs. 3.0 g/L [p=0.0004]); similar differences were seen in levels of CXCL8 (CF patients=10.2 pg/mL and controls=5.9 pg/mL [p=0.0065]). A trend was noted for CC-16, CXCL1, and SP-D. As expected, lung functions assessed by spirometry and IOS values were significantly different in the patient population compared to the control group. Mean FEV1 and mean reactance were 2.4L (67% predicted) vs. 3.5L (99% predicted) and 0.174 kPa/(L/sec) vs. –0.085 kPa/(L/sec) in CF patients vs, controls, respectively(p=0.0002 and p<0.0001)). No age or gender trends were noted among CF patients or controls.

Conclusions: The study demonstrated elevation of CXCR2 agonists in stable patients with CF. We also confirmed the potential utility of IOS, an effort-independent lung function test. Finally, the study suggests that subject matching for age and gender may not be necessary in future CF trials assessing these biomarkers.

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