Translational control during the acute phase response. Ferritin synthesis in response to interleukin-1.

Interleukin-1 (IL-1 beta) increases the synthesis of both heavy and light (L)-ferritin subunits when added to human hepatoma cells (HepG2) grown in culture. RNase protection and Northern blot analysis with L-ferritin probes revealed that no changes in L-ferritin mRNA levels occur after cytokine stimulation. However, the induction coincides with an increased association of the L-subunit mRNA with polyribosomes. Since the recruitment of stored ferritin mRNA onto polyribosomes is seen when iron enters the cell, the effect of IL-1 beta on iron uptake was tested and was found to be unaffected by the lymphokine. Neither transferrin receptor mRNA levels nor the number of receptors displayed on the cell surface was affected by IL-1 beta. However, the action of the cytokine on ferritin translation is inhibited by the action of the intracellular iron chelator deferoxamine. These data indicate that IL-1 beta induces ferritin gene expression by translational control of its mRNA. The pathway of induction is different from iron-dependent ferritin gene expression whereas regulation requires the background presence of cellular iron.     

Elastin protein levels are a vital modifier affecting normal lung development and susceptibility to emphysema

Cigarette smoking is the strongest risk factor for emphysema. However, sensitivity to cigarette smoke-induced emphysema is highly variable, and numerous genetic and environmental factors are thought to mitigate lung response to injury. We report that the quantity of functional elastin in the lung is an important modifier of both lung development and response to injury. In mice with low levels of elastin, lung development is adversely affected, and mice manifest with congenital emphysema. Animals with intermediate elastin levels exhibit normal alveolar structure but develop worse emphysema than normal mice following cigarette smoke exposure. Mechanical testing demonstrates that lungs with low levels of elastin experience greater tissue strains for any given tissue stress compared with wild-type lungs, implying that force-mediated propagation of lung injury through alveolar wall failure may worsen the emphysema after an initial enzymatic insult. Our findings suggest that quantitative deficiencies in elastin predispose to smoke-induce emphysema in animal models and suggest that humans with altered levels of functional elastin could have relatively normal lung function while being more susceptible to smoke-induced lung injury.     

Viral respiratory infection increases susceptibility of young rats to hypoxia-induced pulmonary edema

Recentclinical observations of a high incidence of preexisting respiratoryinfections in pediatric cases of high-altitude pulmonary edema promptedus to ask whether such infections would increase the susceptibility tohypoxia-induced pulmonary edema in young rats. We infected weanlingrats with Sendai virus, thus causing a mild respiratory infection.Within 7 days of infection, Sendai virus was essentially undetectableby using viral culture and immunohistochemical techniques. Animals atday 7 of Sendai virus infection werethen exposed to normobaric hypoxia (fraction of inspiredO₂ = 0.1) for 24 h and examinedfor increases in gravimetric lung water and in vascular permeability,as well as for histological evidence of increased lung water.Bronchoalveolar lavage was performed on a separate series of animals.Compared with control groups, infected hypoxic animals showedsignificant increases in perivascular cuffing, gravimetric lung water,and lung protein leak. In addition, infected hypoxic animals hadincreases in lavage fluid cell counts and protein content compared withcontrols. We conclude that young rats, exposed to moderate hypoxiawhile recovering from a mild viral respiratory infection, maydemonstrate evidence of early pulmonary edema formation, a finding ofpotential relevance to human high-altitude pulmonary edema.