Nitroglycerin alters alveolar type II cell ultrastructure after ischemia and reperfusion.
BACKGROUND
Although administration of nitric oxide (NO) has been suggested to reduce pulmonary reimplantation response, concerns remain about cytotoxic side effects.


METHODS
Using light and electron microscopy, we examined the effects of the NO donor nitroglycerin (NTG) (0.1 mg/ml) as a supplement to the preservation solution Celsior on the structural integrity of rat lungs after extracorporeal ischemia (4 hours at 10 degrees C) and reperfusion (50 minutes) (IR). We performed evaluation in comparison with Celsior alone after IR using either standard antegrade perfusion through the pulmonary artery or retrograde perfusion through the left atrium as an alternative way to improve the preservation quality. Untreated, non-ischemic lungs served as controls (n = 5 per group). We recorded respiratory and hemodynamic parameters during reperfusion. Tissue collection using systematic uniform random sampling was representative for the whole organ and allowed stereologic quantification of structures.


RESULTS
After IR, histochemistry revealed no breaks in the alveolo-capillary barrier and we detected no alveolar flooding. Edema formed in the peribronchovascular cuffs, of which the volume fraction was increased (p =.008). Vasoconstriction of the smaller arteries accompanied antegrade flush, which occurred neither after administration of NTG nor after retrograde flush, as shown by immunostaining for alpha-smooth muscle actin. Treatment with NTG was associated with focal disintegration of Type II cells, which displayed edematous swelling of distinct cell compartments and lysis of mitochondria and cells. Nitroglycerin prevented alveolar collapse, which was increased in the other IR groups (p = 0.013). We observed alterations in intra-alveolar surfactant components.


CONCLUSIONS
These findings indicate pathologic effects of NTG treatment on alveolar epithelial integrity. Therefore, we suggest further critical evaluation of NTG/NO for therapeutic use in lung transplantation.
Fehrenbach
A
A
Division of Electron Microscopy, Center of Anatomy, University of Göttingen, Göttingen, Germany. afehren1@gwdg.de
Wittwer
T
T
Meyer
D
D
von Vietinghoff
S
S
Viehöver
M
M
Fehrenbach
H
H
Richter
J
J
Wahlers
T
T
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D004187:Disaccharides; D004573:Electrolytes; D004848:Epithelium / Q000187:drug effects / Q000473:pathology; D005971:Glutamates; D005978:Glutathione; D006639:Histidine; D008168:Lung / Q000098:blood supply*; D016040:Lung Transplantation / Q000502:physiology*; D008297:Male; D008353:Mannitol; D008854:Microscopy, Electron; D009569:Nitric Oxide / Q000502:physiology / Q000633:toxicity*; D005996:Nitroglycerin / Q000633:toxicity*; D011650:Pulmonary Alveoli / Q000187:drug effects* / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000473:pathology*
C088453:Celsior; D004187:Disaccharides; D004573:Electrolytes; D005971:Glutamates; D009569:Nitric Oxide; D008353:Mannitol; D006639:Histidine; D005996:Nitroglycerin; D005978:Glutathione