For evaluation of the ontogenetic regulation of the acute phase response, inflammation was induced in Fischer rat litters at different postnatal ages. Four homologous rat hepatic serine protease inhibitor (Spi 2.1, Spi 2.2, Spi 2.3, and α1-antitrypsin) mRNAs were measured in livers 24 h after injection. Animals mounted both positive and negative acute phase responses at all ages, but responses were blunted in young animals, reaching adult levels by days 7-19. α1-Antitrypsin mRNA had no response, and Spi 2.2 mRNA had 50% the rise seen in adults on days 3 and 7. Spi 2.1 and 2.3 mRNAs, negative acute phase reactants, showed attenuation of adult response to inflammation in infant animals of 33% (Spi 2.1) and 40% (Spi 2.3). In hypophysectomized animals, the responses of Spi 2.2, 2.3, and α1-antitrypsin mRNAs after turpentine stimulation were similar to that of normal animals, whereas Spi 2.1 mRNA did not change. In conclusion, infant animals mount a blunted response to tissue injury; multiple factors may be involved in the development of the full adult response. Immaturity of the pituitary may play a role in the suppression of Spi 2.1 mRNA's response during inflammation in infant animals. These highly evolutionary related genes will be helpful in identifying specific factors regulating gene expression in inflammation and development.