Inducible nitric oxide synthase/CD95L-dependent suppression of pulmonary and bone marrow eosinophilia by diethylcarbamazine.
BACKGROUND
The mechanism of action of diethylcarbamazine (DEC), an antifilarial drug effective against tropical pulmonary eosinophilia, remains controversial. DEC effects on microfilariae depend on inducible NO synthase (iNOS). In eosinophilic pulmonary inflammation, its therapeutic mechanism has not been established. We previously described the rapid up-regulation of bone marrow eosinophilopoiesis in ovalbumin (OVA)-sensitized mice by airway allergen challenge, and further evidenced the down-regulation of eosinophilopoiesis by iNOS- and CD95L-dependent mechanisms.


OBJECTIVE
We investigated whether: (1) DEC can prevent the effects of airway challenge of sensitized mice on lungs and bone marrow, and (2) its effectiveness depends on iNOS/CD95L.


METHODS
OVA-sensitized BALB/c mice were intranasally challenged for 3 consecutive days, with DEC administered over a 12-, 3-, or 2-day period, ending at the day of the last challenge. We evaluated: (1) airway resistance, cytokine (IFN-gamma, IL-4, IL-5, and eotaxin) production, and pulmonary eosinophil accumulation; and (2) bone marrow eosinophil numbers in vivo and eosinophil differentiation ex vivo.


RESULTS
DEC effectively prevented the effects of subsequent challenges on: (1) airway resistance, Th1/Th2 cytokine production, and pulmonary eosinophil accumulation; and (2) eosinophilopoiesis in vivo and ex vivo. Recovery from unprotected challenges included full responses to DEC during renewed challenges. DEC directly suppressed IL-5-dependent eosinophilopoiesis in naive bone marrow. DEC was ineffective in CD95L-deficient gld mice and in mice lacking iNOS activity because of gene targeting or pharmacological blockade.


CONCLUSIONS
DEC has a strong impact on pulmonary eosinophilic inflammation in allergic mice, as well as on the underlying hemopoietic response, suppressing the eosinophil lineage by an iNOS/CD95L-dependent mechanism.
Queto
Tulio
T
Laboratório de Fisiopatologia Humana, IFF, FIOCRUZ, Rio de Janeiro, Brazil.
Xavier-Elsas
Pedro
P
Gardel
Marcelo Aranha
MA
de Luca
Bianca
B
Barradas
Mônica
M
Masid
Daniela
D
E Silva
Patricia Machado R
PM
Peixoto
Christina A
CA
Vasconcelos
Zilton Meira F
ZM
Dias
Eliane P
EP
Gaspar-Elsas
Maria Ignez
MI
D000403:Airway Resistance / Q000187:drug effects; D000818:Animals; D001855:Bone Marrow Diseases / Q000188:drug therapy*; D016085:Bronchoconstrictor Agents / Q000494:pharmacology; D004049:Diethylcarbamazine / Q000494:pharmacology*; D004802:Eosinophilia / Q000188:drug therapy*; D004804:Eosinophils / Q000187:drug effects; D053222:Fas Ligand Protein / Q000502:physiology*; D005369:Filaricides / Q000494:pharmacology*; D006410:Hematopoiesis / Q000187:drug effects; D007371:Interferon-gamma / Q000096:biosynthesis; D015847:Interleukin-4 / Q000096:biosynthesis; D015848:Interleukin-5 / Q000096:biosynthesis; D018655:Lymphocyte Count; D016210:Methacholine Chloride / Q000494:pharmacology; D051379:Mice; D008807:Mice, Inbred BALB C; D052247:Nitric Oxide Synthase Type II / Q000502:physiology*; D011657:Pulmonary Eosinophilia / Q000188:drug therapy*
D016085:Bronchoconstrictor Agents; D053222:Fas Ligand Protein; D005369:Filaricides; D015848:Interleukin-5; D016210:Methacholine Chloride; D015847:Interleukin-4; D007371:Interferon-gamma; D052247:Nitric Oxide Synthase Type II; D004049:Diethylcarbamazine