pulmonary vascular remodeling

Pulmonary vascular remodeling is associated with increased pulmonary vascular resistance, pulmonary artery hypertension (PAH), and right heart failure.

Advanced PAH is characterized by arteriopathy, which includes muscularization of distal pulmonary arterioles, concentric intimal thickening, and obstruction of the vascular lumen by proliferating endothelial cells to form plexiform lesions.

PAH is associated with genetic perturbations favoring cellular growth, proliferation, and angiogenesis and inhibitors of apoptosis, previously thought to be only expressed in cancer cells, promoting a proliferative cellular phenotype, resulting in pulmonary vascular remodeling in PAH.

The histopathologic features and known genetic susceptibilities of this condition have led to the hypothesis that PAH arises from hyperproliferation of pulmonary artery smooth muscle cells (PASMCs) and endothelial cells (PAECs).

In addition to the formation of proliferative neointimal lesions and muscularization of the pulmonary vascular bed, perivascular inflammatory cell infiltrates are also present in advanced human cases of PAH.

These infiltrates consist of T cells, B cells, and macrophages, suggesting that cytokines and growth factors associated with these inflammatory cells may be promoting PAEC and PASMC hyperproliferation.

The proinflammatory cytokine interleukin (IL)-6 is consistently increased in the serum and lungs6–8 of patients with idiopathic PAH and in inflammatory diseases that are associated with PAH.

In addition, Kaposi sarcoma–associated herpes virus, which may cause PAH in human immunodeficiency virus–negative Castleman’s disease, encodes a constitutively active form of IL-6 resulting in unregulated cell growth and escape from host antitumor defenses.

Furthermore, unchecked production of IL-6 in tissues leading to chronic inflammation has exhibited a strong association with many cancers.

References

 Interleukin-6 overexpression induces pulmonary hypertension. Steiner MK, Syrkina OL, Kolliputi N, Mark EJ, Hales CA, Waxman AB. Circ Res. 2009 Jan 30;104(2):236-44, 28p following 244. PMID: 19074475