Deficiency in the divalent metal transporter 1 increases bleomycin-induced lung injury

Abstract

Exposure to bleomycin can result in an inflammatory lung injury. The biological effect of this anti-neoplastic agent is dependent on its coordination of iron with subsequent oxidant generation. In lung cells, divalent metal transporter 1 (DMT1) can participate in metal transport resulting in control of an oxidative stress and tissue damage. We tested the postulate that metal import by DMT1 would participate in preventing lung injury after exposure to bleomycin. Microcytic anemia (mk/mk) mice defective in DMT1 and wild-type mice were exposed to either bleomycin or saline via intratracheal instillation and the resultant lung injury was compared. Twenty-four h after instillation, the number of neutrophils and protein concentrations after bleomycin exposure were significantly elevated in the mk/mk mice relative to the wild-type mice. Similarly, levels of a pro-inflammatory mediator were significantly increased in the mk/mk mice relative to wild-type mice following bleomycin instillation. Relative to wild-type mice, mk/mk mice demonstrated lower non-heme iron concentrations in the lung, liver, spleen, and splenic, peritoneal, and liver macrophages. In contrast, levels of this metal were elevated in alveolar macrophages from mk/mk mice. We conclude that DMT1 participates in the inflammatory lung injury after bleomycin with mk/mk mice having increased inflammation and damage following exposure. This finding supports the hypothesis that DMT1 takes part in iron detoxification and homeostasis in the lung.

Smoking-induced iron dysregulation in the lung

“…Interestingly, bleomycin directly complexes redox-active iron resulting in DNA degradation and iron deficiency or chelation is associated with a reduction in the severity of bleomycin-induced pulmonary fibrosis. Similarly, an iron-depleted diet diminishes fibrotic injury after dust instillation, whereas loss of DMT1 increases bleomycin-induced lung injury [150][151][152][153][154]. Another recent study showed that a FPN1 mutation resulted in iron accumulation in AMs and lung epithelial cells with subsequent development of restrictive lung disease [155].…”

Iron in Lung Pathology

“…The Belgrade rat, an animal model of functional DMT1 deficiency, develops more severe lung injury in response to lipopolysaccharide (LPS) and oil fly ash [23,24]. Similarly, mk / mk mice, also defective in DMT1, have increased bleomycin-induced lung injury compared to wild-type controls [25]. The mechanism of DMT1 attenuating the lung’s response to inflammatory stimuli is unclear, but these descriptive studies demonstrate a link between DMT1 and the lung’s inflammatory response.…”