Drotrecogin alfa (activated) prevents smoke-induced increases in pulmonary microvascular permeability and proinflammatory cytokine IL-1beta in rats.
In an established rat model of smoke inhalation injury, we conducted a dose-response study to examine the protective effects of Xigris [drotrecogin alfa (activated) (DrotAA)], a recombinant form of human activated protein C (APC). DrotAA is a serine protease (approximately 55 kD molecular weight) with the same amino acid sequence and the glycosylation site as human plasma-derived APC. A total of 120 F344/NH rats (half each gender, approximately 175 g body weight) were randomly divided into five groups and exposed nose-only to air or diesel fuel smoke for 20 min. These rats were then i.v. administered with DrotAA in 0, 5, 10, and 20 mg/kg body weight, respectively, immediately following smoke exposure. Treatment with DrotAA significantly attenuated smoke inhalation injury in a dose-dependent manner at 2 hours after insult, as indicated by preserving microvascular permeability and proinflammatory cytokine IL-1beta (but not TNF-alpha and neuropeptide substance P) in bronchoalveolar lavage fluid (BALF). Moreover, the rats treated with 20 mg/ kg of DrotAA had an improvement of the expiration phase of pulmonary dynamic compliance. At all dosages, however, DrotAA also significantly increased all phases of pulmonary resistance compared with either the controls or to smoke inhalation alone. Generally, these data suggest that DrotAA may exert an anti-inflammatory effect by inhibiting cytokine-mediated inflammatory amplification. However, additional studies following a clinical course are needed to confirm the maximum efficiency and possible side effects of this recombined human activated protein C.
Wong
S S
SS
Lung Injury Laboratory, Department of Pediatrics, The University of Arizona Health Sciences Center, Tucson, Arizona 85724, USA.
Sun
N N
NN
Hyde
J D
JD
Ruiz
L
L
Meigs
E
E
Herrin
B R
BR
Fastje
C D
CD
Macdonald
S J
SJ
Witten
M L
ML
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry; D002199:Capillary Permeability / Q000187:drug effects*; D016207:Cytokines / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005260:Female; D007375:Interleukin-1 / Q000378:metabolism*; D008168:Lung / Q000098:blood supply / Q000503:physiopathology; D008297:Male; D011486:Protein C / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344; D011994:Recombinant Proteins / Q000627:therapeutic use*; D012906:Smoke / Q000009:adverse effects; D015208:Smoke Inhalation Injury / Q000517:prevention & control*; D013373:Substance P / Q000032:analysis; D013997:Time Factors
D000894:Anti-Inflammatory Agents, Non-Steroidal; D016207:Cytokines; D007375:Interleukin-1; D011486:Protein C; D011994:Recombinant Proteins; D012906:Smoke; D013373:Substance P; C421124:drotrecogin alfa activated