SUMMARY. BACKGROUND: Several aspects of the inflammatory response to a single insult, i.e., exposure to 2 ppm of ozone (O3) for 3 h or 6 h, are less pronounced in surfactant protein A deficient (SP-A -/-) mice (KO) than in wild type mice (WT). It was hypothesized that a mild insult, specifically low doses of lipopolysaccharide (LPS), would adversely affect host defense and differentially potentiate O3-induced injury in WT and KO mice. METHODS: WT and KO mice were treated with different doses of LPS or LPS (2 ng) + O3 (2 ppm) or filtered air (FA) for 3 h, then sacrificed 4 h following exposure (O3, FA) or 20 h after LPS treatment alone. Several endpoints of inflammation were measured in bronchoalveolar lavage (BAL). RESULTS: 1) At 20 h after LPS treatment alone, both WT and KO mice exhibited signs of inflammation, but with differences in the macrophage inflammatory protein 2 (MIP-2) response pattern, total cells (at 0.5 ng LPS) and basal levels of oxidized protein and phospholipids; 2) After LPS + O3, KO compared to WT showed decrease in polymorphonuclear leukocytes (PMNs) and MIP-2 and increase in phospholipids, and after LPS + FA an increase in total cells; 3) WT after LPS + FA showed an increase in SP-A with no further increase after LPS + O3, and an increase in oxidized SP-A dimer following O3 or LPS + O3. CONCLUSIONS: LPS treatment has negative effects on inflammation endpoints in mouse BAL long after exposure and renders KO mice less capable of responding to a second insult. LPS and O3 affect SP-A, quantitatively and qualitatively, respectively. Pneumon 2009; 22(2):143-155 “Duty is liberating. It forces you to transcend your own limitations and makes you do things that may not come naturally, but must be done, because they are right.” David Rockefeller