Complement partially mediates acid aspiration-induced remote organ injury in the rat.
BACKGROUND
Acid aspiration into one lung is known to cause both a local as well as remote organ injury characterized by neutrophil sequestration and subsequent edema. This study investigated investigated the role of the complement cascade in the development of acid aspiration-induced local lung and remote organ injuries using K-76 COONa (K76), an anticomplement agent that inhibits the complement pathway at the C5 step, and its usefulness as a treatment drug.


METHODS
Anesthetized rats underwent tracheostomy and insertion of a cannula. K76 was intraperitoneally administrated prior to or immediately after the instillation of 0.1 ml of HCl (0.1N) or phosphate buffer solution (PBS) into the left lung. Inflammatory responses were evaluated by tumor necrosis factor alpha (TNF alpha) in the plasma and the bronchoalveolar lavage fluid (BALF) (n = 4), tissue myeloperoxidase (MPO), wet-to-dry weight ratio (W/D ratio) (n = 6), and protein concentration in the BALF (n = 6).


RESULTS
Acid instillation caused an increase in the plasma TNF alpha, which was significantly attenuated by the administration of K76 prior to or after the acid instillation. Acid instillation to the left lung resulted in an increase of MPO and W/D ratios of the left lung, the right lung, and the small intestine. The administration of K76 inhibited the increase of MPO in these organs. K76 inhibited the increase of W/D ratios of the right non-instillated lung and the small intestine. Acid instillation led to increased protein concentration in the BALF of the left lung, which was not inhibited by K76. K76 administrated after the acid instillation had the same effects. TNF alpha in the BALF was not detected in all groups.


CONCLUSIONS
These results suggest that localized acid aspiration induces, through the C5a step of the complement system-dependent mechanisms, TNF alpha formation and neutrophil sequestration, which caused the increase of endothelial permeability of the systemic organs. K76 is effective as a treatment drug in modulating some of the injuries caused by the acid instillation, but further investigations is warranted as to its potential as a therapeutic agent.
Yamada
H
H
Department of Anesthesiology, Yokohama City University School of Medicine, Japan.
Kudoh
I
I
Nishizawa
H
H
Kaneko
K
K
Miyazaki
H
H
Ohara
M
M
Okumura
F
F
D000818:Animals; D015936:Complement C5a / Q000502:physiology; D003165:Complement System Proteins / Q000502:physiology*; D006877:Hydroxamic Acids / Q000494:pharmacology; D008168:Lung / Q000201:enzymology; D016177:Macrophage-1 Antigen / Q000502:physiology; D008297:Male; D009929:Organ Size; D009195:Peroxidase / Q000378:metabolism; D011015:Pneumonia, Aspiration / Q000150:complications*; D051381:Rats; D017208:Rats, Wistar; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D006877:Hydroxamic Acids; D016177:Macrophage-1 Antigen; D014409:Tumor Necrosis Factor-alpha; C003486:2-methyl-3-(4-phenylpiperidino)propionohydroxamic acid hydrochloride; D015936:Complement C5a; D003165:Complement System Proteins; D009195:Peroxidase