MAIN RESULTS:

1. Hypoxia activates inflammasomes and increases inflammation in mice lungs.
2. The inflammasome adaptor protein ASC mediates hypoxia-induced pulmonary artery remodeling.
3. Interleukin-18 inhibition reduces cardiac remodeling and dysfunction in healthy mice.

THESIS DEFENCE:

Thesis: Hypoxia-Induced Pulmonary Hypertension and Cardiac Dysfunction; The Role of Inflammasomes and related Cytokines
Candidate: Fadila Telarevic Cero
Time: December 6, 2019 at 13:15
Place: Oslo University Hospital, Ullevål, Kreftsenteret: Auditorium 1
Link to university website

SUMMARY:

(1) The receptor for the proinflammatory cytokine interleukin-18 is more highly expressed in lung tissue than other organs. The interleukin-12 receptor is also present in the lungs. Injections with interleukin-18 and interleukin-12, alone as well as combined, activate enzymes that degrade lung matrix in healthy mice and are associated with emphysema. Such injections also induces cellular apoptosis in lung tissue and infiltration of T-cells in the lungs.

(2) Hypoxia activates inflammasomes and leads to higher levels of caspase-1, interleukin-18 and interleukin-1β. The mice in the study were exposed to four weeks of hypoxia. Neutrophils infiltrated the lung vasculature the first three days, followed by increased infiltration of T-cells during the latter half of the first week. At four weeks, the levels of interleukin-18 were still significantly increased compared to controls, whereas interleukin-1β was non-significantly upregulated.

(3) Hypoxia induces pulmonary hypertension, remodeling of the right ventricle and impaired filling of the left ventricle. The pulmonary artery remodeling is mediated by the inflammasome adaptor protein ASC, evidenced by the attenuated development of pulmonary hypertension in mice lacking this component. These mice also had no increase of active caspase-1, interleukin-18 or interleukin-1β following three months of hypoxia.

(4) An interleukin-18 inhibitor resulted in lower right ventricular remodeling and improved filling of the left ventricle in healthy mice exposed to hypoxia. This improvement was closely linked to normalized calcium-handling in the heart.

REFERENCES:

(1) Cero, F. T., Hillestad, V., Løberg, E. M., Christensen, G., Larsen, K. O., & Skjønsberg, O. H. (2012). IL-18 and IL-12 synergy induces matrix degrading enzymes in the lung. Experimental lung research, 38(8), 406-419.

(2) Cero, F. T., Larsen, K. O., Christensen, G., & Skjønsberg, O. H. Hypoxia induces inflammasome activation and influx of neutrophils and T-cells in the lungs.

(3) Cero, F. T., Hillestad, V., Sjaastad, I., Yndestad, A., Aukrust, P., Ranheim, T., Lunde, I. G., Olsen, M. B., Lien, E., Zhang, L., Haugstad, S. B., Løberg, E. M., Christensen, G., Larsen, K.-O., & Skjønsberg, O. H. (2015). Absence of the inflammasome adaptor ASC reduces hypoxia-induced pulmonary hypertension in mice. American Journal of Physiology-Lung Cellular and Molecular Physiology, 309(4), L378-L387.