Nicotine enhances skin necrosis and expression of inflammatory mediators in a rat pressure ulcer model.
BACKGROUND
Many bedridden patients develop pressure ulcers, not only in hospital but also at home. Clinical studies have indicated cigarette smoking to be a risk factor for pressure ulcers. However, the contribution of nicotine to pressure ulcer formation has not been identified.


OBJECTIVE
We aimed to clarify the effect of nicotine on pressure ulcer formation, and its mechanism.


METHODS
Ischaemia-reperfusion (I/R) was performed in rat dorsal skin to induce pressure ulcers. The extent of the resulting necrotic area was determined. To clarify the mechanism of the effect of nicotine, mRNA levels of cyclooxygenase-2 (COX-2), interleukin (IL)-1beta, IL-6 and inducible nitric oxide synthase (iNOS) and protein expression of COX-2 and iNOS in the necrotic area were investigated by real-time reverse transcription-polymerase chain reaction and Western blotting, respectively. Furthermore, the effects of the COX-2 inhibitor NS-398 and the iNOS inhibitor aminoguanidine on necrosis were examined.


RESULTS
Skin necrosis in the I/R-treated area was significantly increased by intraperitoneal administration of nicotine (0.175 mg kg(-1) daily). Repeated nicotine administration had little effect on systolic and diastolic blood pressure. I/R treatment increased mRNA levels of COX-2, IL-1beta, IL-6 and iNOS, which were further augmented by nicotine in a dose-dependent manner. Correspondingly, nicotine (0.35 mg kg(-1) daily) markedly enhanced the protein expression of COX-2 and iNOS. Moreover, NS-398 and aminoguanidine showed a tendency to abrogate the increase of I/R-induced skin necrosis caused by nicotine.


CONCLUSIONS
These results suggest that the increased risk of pressure ulcers due to cigarette smoking is mediated, in part, by nicotine. They also indicated that the effect of nicotine is not mediated by a change in blood pressure, but is elicited via an increase of inflammatory mediators in the I/R-treated skin.
Tsutakawa
S
S
Department of Cellular Signalling, Graduate School of Pharmaceutical Science, Tohoku University, Aoba 6-3, Aramaki, Aoba-ku, Sendai 980-8578, Japan.
Kobayashi
D
D
Kusama
M
M
Moriya
T
T
Nakahata
N
N
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D053583:Interleukin-1beta / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000378:metabolism*; D008297:Male; D023421:Models, Animal; D009336:Necrosis; D009538:Nicotine / Q000009:adverse effects*; D018722:Nicotinic Agonists / Q000009:adverse effects*; D052247:Nitric Oxide Synthase Type II / Q000235:genetics / Q000378:metabolism*; D003668:Pressure Ulcer / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000150:complications; D012867:Skin / Q000473:pathology
D053583:Interleukin-1beta; D015850:Interleukin-6; D007378:Interleukins; D018722:Nicotinic Agonists; D012333:RNA, Messenger; D009538:Nicotine; D052247:Nitric Oxide Synthase Type II; D051546:Cyclooxygenase 2