Surfactant protein B (SP-B) is known to promote surfactant phospholipid film formation and reduce surface tension. Native SP-B is a homodimer in which subunit association is stabilized via covalent linkage through cysteine 48. We hypothesized that loss of the inter-subunit bridge would alter SP-B function leading to increased inflammation in response to challenge by hyperoxia or endotoxin. Transgenic mice in which SP-B cysteine 48 was mutated to serine were generated and crossed into the SP-B(-/-) background. Wild type mice and transgenic mice carrying a single copy (SP-Bmon⁺) or two copies (SP-Bmon⁺⁺) of the transgene were exposed to 95% 0₂ for 3d or intra-tracheally injected with 10 µg of endotoxin. IL-1ß, MIP-2 and IL-6 in lung homogenates after 3d of hyperoxia were significantly higher (p<0.001) in SP-Bmon⁺ mice than SP-Bmon⁺⁺ or wild type mice. At 16h after endotoxin injection, cytokines in lung tissues were higher in SP-Bmon⁺ mice compared to wild type mice (p<0.05). Consistent with prolonged recovery in SP-Bmon⁺ mice, the percentage of apoptotic cells in alveolar lavage was significantly lower in SP-Bmon⁺ mice than SP-Bmon⁺⁺ and wild type mice. Overall, increased inflammation in SP-Bmon⁺ mice was corrected to a large extent by increased gene dosage indicating that formation of the inter-subunit disulfide bridge is not critical for SP-B function.