Pharmacologic stimulation of the nicotinic anti-inflammatory pathway modulates gut and lung injury after hypoxia-reoxygenation injury.
OBJECTIVE
Pre-injury vagal nerve stimulation protects against gut and lung injury after experimental hemorrhagic shock (HS). This likely occurs via the cholinergic anti-inflammatory pathway and the α7 nicotinic acetylcholine receptor (α7nAChR). We hypothesized that, in an in vitro model, either nicotine or a selective α7nAChR agonist (AR-R17779) would modulate intestinal and pulmonary effects of gut ischemia-reperfusion after hypoxic insult.


METHODS
Confluent HT29 intestinal epithelial cells were co-cultured with Escherichia coli. Cell cultures were subjected to 21% (control) or 5% O2 (hypoxia) for 90 minutes followed by reoxygenation (H/R). HT29 cells were treated with nicotine or AR-R17779 before or immediately after hypoxic insult. From the HT29 cell culture supernatants, tumor necrosis factor-α and interleukin-6 levels were quantitated. Confluent pulmonary microvascular epithelial cells (HMVEC) were co-cultured with HT29 supernatants and permeability and intercellular adhesion molecule-1 expression were determined.


RESULTS
In post H/R insult treatments with the receptor agonist, cytokine levels in HT29 cells were reduced to control levels. In HMVEC experiments, a protective effect was seen with treatment post H/R injury. Disruption of HT29 actin microfilaments was demonstrated after H/R insult and was abrogated by both agonists.


CONCLUSIONS
Post-insult pharmacologic stimulation seems to mimic the protective effects of pre-HS vagal nerve stimulation seen in animal studies.
Department of Surgery, Wayne State University, Detroit, MI.
Samantha L
SL
Tarras
Lawrence N
LN
Diebel
David M
DM
Liberati
Kevin
K
Ginnebaugh
D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D015687:Cell Hypoxia; D019073:HT29 Cells; D006801:Humans; D015850:Interleukin-6 / Q000032:analysis; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000098:blood supply*; D055370:Lung Injury / Q000517:prevention & control*; D009538:Nicotine / Q000494:pharmacology*; D015427:Reperfusion Injury / Q000517:prevention & control*; D013141:Spiro Compounds / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis; D014630:Vagus Nerve / Q000502:physiology
C408128:AR-R 17779; D001952:Bridged-Ring Compounds; D015850:Interleukin-6; D013141:Spiro Compounds; D014409:Tumor Necrosis Factor-alpha; D009538:Nicotine