Do human and rat alveolar macrophages share common responses to lung particle overload?

Inhalation of poorly soluble low toxicity particles (PSLT), such as titanium dioxide or carbon black, can induce chronic inflammation and lung cancer in experimental rats, but not in mice, at exposure levels leading to lung particle overload, i.e. a condition associated with altered alveolar macrophage function and mobility. Which experimental response (rat or mouse) is the most predictive for humans exposed to high doses of PSLT has remained unsettled for more than 40 years. These particles have therefore been conservatively classified as possible human carcinogens by regulatory agencies. In order to gain further insight into the possible human carcinogen hazard of PSLT for humans, we compared in vitro the responses to PSLT overload in human, rat and mouse alveolar macrophages by using untargeted transcriptomics. We identified 18 genes significantly differentially expressed in rat alveolar macrophages under overload conditions, with both titanium dioxide and carbon black. The function of these genes appears mostly relevant for macrophage overload, inflammation and cancer development, which is consistent with the outcome of rat in vivo experiments. The degree of modulation of these genes in rat macrophages did not correlate with the modulation of orthologous genes in mouse macrophages, but well with those in human macrophages. In conclusion, alveolar macrophages from rat and human share common adverse responses to overload of PSLT, suggesting a hazard for humans.