IP-10 Is a Potential Biomarker of Cystic Fibrosis Acute Pulmonary Exacerbations

Background: Cystic fibrosis (CF) is characterized by acute pulmonary exacerbations (APE). The CF nasal airway exhibits a similar ion transport defect as the lung, and colonization, infection, and inflammation within the nasal passages are common among CF patients. Nasal lavage fluid (NLF) is a minimally invasive means to collect upper airway samples. Methods: We collected NLF at the onset and resolution of CF APE and compared a 27-plex cytokine profile to stable CF outpatients and normal controls. We also tested IP-10 levels in the bronchoalveolar lavage fluid (BALF) of CF patients. Well-differentiated murine sinonasal monolayers were exposed to bacterial stimulus, and IP-10 levels were measured to test epithelial secretion. Results: Subjects hospitalized for APE had elevated IP-10 (2582 pg/mL [95% CL of mean: 818,8165], N= 13) which significantly decreased (647 pg/mL [357,1174], P< 0.05, N = 13) following antimicrobial therapy. Stable CF outpatients exhibited intermediately elevated levels (680 pg/mL [281,1644], N= 13) that were less than CF inpatients upon admission (P= 0.056) but not significantly different than normal controls (342 pg/mL [110,1061]; P= 0.3, N= 10). IP-10 was significantly increased in CF BALF (2673 pg/mL [1306,5458], N= 10) compared to healthy post-lung transplant patients (8.4 pg/mL [0.03,2172], N= 5, P< 0.001). IP-10 levels from well-differentiated CF murine nasal epithelial monolayers exposed to Pseudomonas PAO-1 bacteria-free prep or LPS (100 nM) apically for 24 hours were significantly elevated (1159 +/- 147, P< 0.001 for PAO-1; 1373 +/- 191, P< 0.001 for LPS vs. 305 +/- 68 for vehicle controls). Human sino-nasal epithelial cells derived from CF patients had a similar response to LPS (34% increase, P< 0.05, N= 6). Conclusions: IP-10 is elevated in the nasal lavage of CF patients with APE and responds to antimicrobial therapy. IP-10 is induced by airway epithelia following stimulation with bacterial pathogens in a murine model. Additional research regarding IP-10 as a potential biomarker is warranted.