An increasing number of studies implicate
heme oxygenase-1 (HO-1) in the regulation of
inflammation. Although the mechanisms involved in this cytoprotection are largely unknown, HO-1 and its enzymatic products,
carbon monoxide and
bilirubin, downregulate the inflammatory response by either attenuating the expression of adhesion molecules and thus inhibiting leukocyte recruitment or by repressing the induction of
cytokines and
chemokines. In the present study we used genetically engineered mice that express high levels of a human
cDNA HO-1 transgene in lung epithelium to assess the effect of HO-1 on
lung inflammation. Two separate models of
inflammation were studied: hypoxic exposure and
lipopolysaccharide (LPS) challenge. We found that both
mRNA and
protein levels of specific
cytokines and
chemokines were significantly elevated in response to
hypoxia in the lungs of wild-type mice after 2 and 5 days of exposure but significantly suppressed in the hypoxic lungs of transgenic mice, suggesting that inhibition of these
cytokines was caused by overexpression of HO-1. However, LPS treatment resulted in a very pronounced increase in
mRNA levels of several
cytokines in both wild-type and transgenic mice. Despite the high
mRNA levels, significantly lower
cytokine protein levels were detected in the bronchoalveolar lavage of HO-1 overexpressing mice compared with wild type, indicating that HO-1 leads to repression of
cytokines in the airway. These results demonstrate that HO-1 activity operates through distinct molecular mechanisms to confer cytoprotection in the hypoxic and the LPS models of
inflammation.