INCREASED EXPRESSION OF TISSUE INHIBITOR OF METALLOPROTEINASES (TIMP-I) AND METALLOTHIONEIN IN MURINE LUNGS AFTER HYPEROXIC EXPOSURE

Acute exposure to hyperoxia results in well-described pathophysiologic responses in the lungs, beginning with subtle, subcellular changes an d ending with severe pulmonary inflammation and edema. The biologic ev ents that underlie or accompany this injury are not well understood. O ur previous studies in rabbits have shown that hyperoxia induces large increases in the mRNAs encoding metallothionein (MT) and the tissue i nhibitor of metalloproteinases (TIMP-I). Here we report studies of hyp eroxic lung injury in two strains of mouse that differ in their relati ve resistance to O2 toxicity. O2-sensitive (C57BL/6J) mice and O2-resi stant (C3H/HeJ) mice were exposed to 100% O2 for up to 96 h. Lung mRNA s were assayed by primer extension and slot blot hybridization. By 72 h of hyperoxia, the sensitive strain showed large increases in MT-I, M T-II, and TIMP-I mRNAs. The resistant strain showed similar changes bu t with a 24-h delay. In situ hybridization demonstrated that hyperoxic lung injury was accompanied by obvious increases in TIMP-I and MT tra nscripts in cells surrounding arteries and large airways, where many i nflammatory cells were localized. With prolonged exposure, hybridizati on to MT transcripts had spread throughout lung parenchyma. The two st rains showed the same patterns of in situ hybridization for TIMP-I and MT transcripts but, as with the whole lung homogenates, followed a di fferent time course. Corresponding increases in MT protein were shown to occur, using a cadmium binding assay and by immunohistochemistry. T he strong spatial correlation between the presence of localized inflam mation and increased TIMP-I and MT expression further supports the imp ortance of TIMP-I and MT in acute lung injury.