Imaging Pulmonary Inducible Nitric Oxide Synthase Expression with PET

Inflammation contributes to many acute and chronic lung diseases. These diseases are associated with high morbidity and mortality rates as well as significant health-care use (1–3). Despite this socioeconomic burden, therapeutic development for respiratory indications lags that of other disease areas (4). This deficiency has been attributed in part to the lack of reliable biomarkers that accurately localize and quantify lung disease activity and assess response to treatment (5). Currently available techniques for assessing lung inflammation include invasive methods such as bronchoalveolar lavage (BAL) and lung tissue biopsy to directly examine immune cells. Induced sputum, although minimally invasive, requires significant patient effort to obtain adequate samples and is difficult to reproduce. Moreover, these tissue-based methods do not provide a global assessment of the inflammatory disease burden or information regarding cellular activity or function. Thus, noninvasive, molecular-based techniques for quantifying inflammation could improve on or provide complementary information to these existing approaches. Several imaging methods have been investigated as potential noninvasive biomarkers for lung inflammation. CT can provide more detailed lung parenchymal characterization for inflammation than plain radiographs (6), but the signal is nonspecific as infiltrates and thickening of the airways can be due to noninflammatory processes, such as edema or hemorrhage. 18F-FDG imaging with PET has been used to measure neutrophilic lung inflammation in patients with acute respiratory distress syndrome, cystic fibrosis, and chronic obstructive pulmonary disease (7–10). However, neoplastic and fibrotic processes also increase glucose utilization, thus decreasing the specificity of 18F-FDG for inflammation. Therefore, there remains a need for novel PET tracers that detect the expression of specific inflammatory markers in lung tissue. Inducible nitric oxide synthase (iNOS, NOS2) is 1 of 3 nitric oxide synthase (NOS) isoforms that is constitutively expressed in normal lung epithelium (11) and is also induced by inflammatory stimuli (12). Increased iNOS has been associated with either disease severity or progression in asthma (13,14), chronic obstructive pulmonary disease (15–17), and acute respiratory distress syndrome (18,19). Preclinical studies also suggest a mechanistic link between iNOS expression and the development of emphysema, pulmonary hypertension, and asthma (20,21). Thus, noninvasive methods for imaging iNOS expression may be useful as a more specific biomarker of inflammatory lung disease activity. We have developed a PET tracer, 18F-NOS, that binds to iNOS (22) and has been used to image iNOS expression in heart transplant recipients (23). To assess its potential utility for imaging lung-related inflammation, we hypothesized that 18F-NOS could image iNOS expression in human lungs after endotoxin instillation.