Upregulation of substance P receptors in angiogenesis associated with chronic airway inflammation in rats

-In rat airways, substance P released from sensory nerves induces plasma leakage via neurokinin-1 (NK₁ ) receptors on endothelial cells. In pathogenfree rats, both leakage and endothelial NK₁ receptors are most abundant in postcapillary venules. In Mycoplasma pulmonis-infected rats, extensive angiogenesis occurs in the tracheal mucosa. The capillary-sized (<10 μm in diameter) angiogenic blood vessels are abnormally sensitive to substance P. The aim of this study was to determine whether increased expression of NK₁ receptors contributes to this abnormal sensitivity. Fischer 344 rats were infected with M. pulmonis and were challenged with substance P (5 μg/kg iv), and then plasma leakage in the tracheal mucosa was measured by extravasation of Monastral blue (30 nig/kg iv). NK₁ receptors on endothelial cells were localized by immunohistochemistry. Five minutes after substance P, NK₁ receptorimmunoreactive endosomes were five times more abundant in endothelial cells of angiogenic capillaries in M. pulmonisinfected rats than in corresponding capillaries in pathogenfree controls (17.1 ± 2.3 vs. 3.5 ± 0.4 endosomes/100 μm² of endothelial surface). Endosomes were slightly more abundant in postcapillary venules 15-35 μm in diameter in infected rats (23.0 ± 0.6 vs. 19.2 ± 0.7 endosomes/100 μm²). Similarly, after substance P, angiogenic capillaries had much more Monastral blue labeling (area density: 18.8 ± 1.5 vs. 2.9 ± 0.5% of vessel wall), whereas postcapillary venules had about the same amount of labeling (36.0 ± 3.7 vs. 34.1 ± 1.8%). We conclude that increased expression of NK₁ receptors, which are internalized into endosomes after ligand binding, contributes to the abnormal sensitivity of endothelial cells of angiogenic blood vessels to substance P in the airways of M. pulmonis-infected rats.