The pulmonary host response to infection and inflammation appears, at least
in part, to be compartmentalized from the systemic host response. Tumor ne
crosis factor-alpha (TNF-alpha) has been implicated in lung inflammation an
d injury, but its site(s) of action has not been clearly defined. To invest
igate this, transgenic mice (surfactant apoprotein C promotor/soluble TNF r
eceptor type II-Fc fusion protein ([SPCTNFRIIFc] mice) were generated in wh
ich TNF-alpha. was selectively antagonized in the distal lung through tissu
e-specific expression of sTNFRIIFc, a soluble TNF inhibitor. The lung infla
mmatory response in these mice to pulmonary challenge with Micropolyspora f
aeni antigen or lipopolysaccharide (LPS) was compared with the response of
wild-type mice, wild-type mice treated with recombinant sTNFRIIFc intraveno
usly, and type I TNF-receptor knockout mice. Recruitment of polymorphonucle
ar leukocytes (PMN) to the lung after challenge with M. faeni antigen was e
ssentially abolished in the TNFRI knockout mice and markedly reduced in the
SPCTNFRIIFc mice. Wild-type mice given sTNFRIIFc intravenously in amounts
resulting in lung concentrations similar to those in SPCTNFRIIFc mice also
showed significantly reduced lung PMN recruitment, whereas those given dose
s that achieved such concentrations in the blood but low levels in the lung
did not. In contrast, PMN recruitment to the lung following aerosol challe
nge with LPS was reduced significantly in the TNFRI knockout mice and in mi
ce given high-dose sTNFRIIFc intravenously, but was not reduced significant
ly in SPCTNFRIIFc mice. Thus, inhibition of PMN recruitment in response to
M. faeni antigen correlated largely with the extent of intrapulmonary inhib
ition of TNF-alpha, whereas the response to LPS correlated best with the ex
tent of extrapulmonary inhibition of TNF-alpha. These studies indicate that
TNF-alpha may act at different loci to mediate lung inflammation, with the
site of action depending in part on the nature of the inflammatory stimulu
s, and that SPCTNFRIIFc mice provide a tool by which the locus of TNF actio
n can be addressed.