UP-REGULATION OF NEUROPEPTIDES AND NEUROPEPTIDE RECEPTORS IN A MURINEMODEL OF IMMUNE INFLAMMATION IN LUNG PARENCHYMA

The lung is richly supplied with peptidergic nerves that store and sec rete substance P (SP), vasoactive intestinal peptide (VIP), and other neuropeptides known to potently modulate leukocyte function in vitro a nd airway inflammation in vivo. To investigate and characterize neurom odulation of immune responses compartmentalized in lung parenchyma, ne uropeptide release and expression of neuropeptide receptors were studi ed in lungs of antigen-primed C57BL/6 mice after intratracheal challen ge with sheep erythrocytes. The concentrations of cytokines in broncho alveolar lavage (BAL) fluid rose early and peaked on day 1 for interle ukin (IL)-2, interferon gamma, and IL-10; days 1 to 2 for IL-6; and da y 3 for IL-4, whereas the total number and different types of leukocyt es in BAL fluid peaked subsequently on days 4 to 6 after i.t. antigen challenge. Immunoreactive SP and VIP in BAL fluid increased maximally to nanomolar concentrations on days 1 to 3 and 2 to 7, respectively in lungs undergoing immune responses. The high-affinity SP receptor (NK- 1 R), and VIP types I (VIPR1) and II (VIPR2) receptors were localized by immunohistochemistry to surface membranes of mononuclear leukocytes and granulocytes in perivascular, peribronchiolar, and alveolar infla mmatory infiltrates during immune responses. As quantified by reverse transcription-polymerase chain reaction, significant increases were ob served in levels of BAL lymphocyte mRNA encoding NK-1 R (days 2 to 4), VIPR1 (days 2 to 4), and VIPR2 (days 4 to 6), and in alveolar macroph age mRNA encoding NK-1 R (days 2 to 6) and VIPR1 (days 2 to 4), but no t VIPR2. Systemic treatment of mice with a selective, nonpeptide NK-1 R antagonist reduced significantly the total numbers of leukocytes, ly mphocytes, and granulocytes retrieved by BAL on day 5 of the pulmonary immune response. The results indicate that SP and VIP are secreted lo cally during pulmonary immune responses, and are recognized by leukocy tes infiltrating lung tissue, and thus their interaction may regulate the recruitment and functions of immune cells in lung parenchyma.