Nicotine attenuates macrophage infiltration in rat lung allografts.
BACKGROUND
Monocytes and macrophages play an important role in acute pulmonary allograft rejection. Acetylcholine has been shown to exert anti-inflammatory effects on these cells via nicotinic acetylcholine receptors. The aim of this study was to test for the hypothesis that a global nicotinic stimulation of pulmonary allograft recipients attenuates acute rejection.


METHODS
Orthotopic left lung transplantation was performed in the Fischer 344-Wistar Kyoto rat strain combination. Graft recipients treated with nicotine added to the drinking water were compared with untreated allograft recipients. Graft histopathology, leukocytic infiltration, expression of inducible nitric oxide (NO) synthase and cytokine expression were analyzed during the process of acute rejection on Day 7 post-transplantation using quantitative reverse transcript-polymerase chain reaction (RT-PCR), enzyme-linked immunoassay (ELISA) and immunohistochemistry. The right native lung of the experimental animals was included as an internal control.


RESULTS
Nicotine treatment resulted in a marked reduction in lung allograft infiltration by CD68-like antigen(+) alveolar and tissue macrophages, whereas resident mature macrophages (CD163(+)) and T cells remained unchanged. Concomitantly, inducible NO synthase expression, which was predominantly localized in alveolar macrophages of control allografts, decreased in response to nicotine. In contrast, cytokine mRNA and peptide levels were only marginally affected by nicotine.


CONCLUSIONS
Stimulation of nicotinic acetylcholine receptors results in a marked attenuation of important hallmarks of pulmonary allograft rejection, indicating that cholinergic therapies may be beneficial for lung allograft recipients.
Laboratory of Experimental Surgery, Department of General and Thoracic Surgery, University of Giessen Lung Center, Justus-Liebig-University Giessen, Giessen, Germany. markus.hirschburger@chiru.med.unigiessen.de
Markus
M
Hirschburger
Anna
A
Zakrzewicz
Wolfgang
W
Kummer
Winfried
W
Padberg
Veronika
V
Grau
D000284:Administration, Oral; D000818:Animals; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D006084:Graft Rejection / Q000276:immunology / Q000473:pathology / Q000517:prevention & control*; D008168:Lung / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D016040:Lung Transplantation / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D016676:Macrophages, Alveolar / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics; D051381:Rats; D011916:Rats, Inbred F344; D011921:Rats, Inbred WKY; D011978:Receptors, Nicotinic / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology
D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D009538:Nicotine; D052247:Nitric Oxide Synthase Type II; C496318:Nos2 protein, rat