Assessment of Microvascular Leakage Via Sputum Induction: the Role of Substance P and Neurokinin A in Patients with Asthma

Microvascular leakage is an important feature of inflammation. However, the assessment of vascular leakage has seldom been used to monitor airway inflammation in asthma. The aim of this study was to determine the effect of inhaled substance P, a potent neurokinin 1 (NK1) agonist and mediator of plasma extravasation, on markers of microvascular leakage in induced sputum from patients with asthma. In a crossover study, sputum was induced before and 30 minutes after inhalation of substance P or neurokinin A (as control) by 12 subjects with atopic and mild, steroid-naive asthma. The levels of alpha2-macroglobulin, ceruloplasmin, albumin, and fibrinogen were determined in induced sputum as markers of leakage. Substance P induced a significant increase in the levels of alpha2-macroglobulin, ceruloplasmin, and albumin in induced sputum (median fold change, 3.1, 2.2, and 2.9, respectively) (p < 0.013), whereas inhaled neurokinin A was not able to induce significant changes (p > 0.31). The increase in sputum leakage markers was not associated with the cumulative dose of substance P (p > 0.12). These results indicate that NK1 receptor stimulation causes a rapid increase in microvascular leakage as shown in induced sputum in patients with asthma. This investigational model of "dual induction" (first leakage, then sputum) may therefore be useful to test the antiexudative effect of newly develop drugs, such as NK1 antagonists.