Suppression of macrophage activation with CNI-1493 increases survival in infant rats with systemic Haemophilus influenzae infection.
CNI-1493, a potent macrophage deactivator, was used to treat infant rats systemically infected with Haemophilus influenzae type b (Hib). CNI-1493 was injected 1 h prior to bacterial inoculation and 24 h later and resulted in a 75 percent increased rate of survival compared to that for untreated controls. The effect of CNI-1493 on the inflammatory response was studied by immunohistochemical detection of individual tumor necrosis factor alpha (TNF-alpha)-, interleukin 1 beta (IL-1beta)-, and gamma interferon (IFN-gamma)-producing cells in the spleen. A significant reduction of the incidence of TNF-alpha- and IL-1beta-expressing cells was found for CNI-1493-treated animals. IFN-gamma expression was not suppressed by CNI-1493, indicating that cytokine inhibition was specific in macrophages. CNI-1493 significantly reduced the number of infiltrating granulocytes in the brain from that for controls. This study provides evidence that CNI-1493 protects against lethal Hib infection by deactivating the inflammatory cascade in infant rats.
Granert
C
C
Division of Infectious Diseases, Department of Medicine, Karolinska Institute, Huddinge University Hospital, Stockholm, Sweden. carl.granert@medhs.ki.se
Abdalla
H
H
Lindquist
L
L
Diab
A
A
Bahkiet
M
M
Tracey
K J
KJ
Andersson
J
J
D000818:Animals; D001921:Brain / Q000187:drug effects; D006098:Granulocytes / Q000187:drug effects / Q000502:physiology; D006192:Haemophilus Infections / Q000188:drug therapy* / Q000276:immunology / Q000401:mortality; D006193:Haemophilus influenzae; D006835:Hydrazones / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000096:biosynthesis; D007375:Interleukin-1 / Q000096:biosynthesis; D008262:Macrophage Activation / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013154:Spleen / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000813:Anilides; D006146:Guanidines
D006835:Hydrazones; D007166:Immunosuppressive Agents; D007371:Interferon-gamma; D007375:Interleukin-1; D014409:Tumor Necrosis Factor-alpha; C097256:semapimod; D000813:Anilides; D006146:Guanidines