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Chronic aortic or mitral valve diseases and left ventricular failure cause increase of pulmonary venous pressure and WHO class-2 pulmonary hypertension (PH). We recently demonstrated that class-2 PH is associated with massive lung remodeling and right ventricular hypertrophy. While it is well recognized that patients with class-2 PH is associated with a worse prognosis, the underlying mechanism of the poor clinical outcome after PH is not clear.
Here, we further studied the effect of chronic aortic restriction on lung structure and function in experimental animals, and the effect of chronic valve diseases on lung consolidation in patients.
We demonstrated that chronic aortic restriction resulted in left ventricular (LV) dysfunction, increases of lung weight and right ventricular weight, as well as their ratios to bodyweight. The profound lung consolidation did not cause lung edema or the percentage of lung water content. The increased lung resistance or reduced lung compliance in mice after aortic stenosis is significantly correlated with the decrease of LV ejection fraction, the increase of lung weight, and right ventricular hypertrophy. Further study demonstrated that aortic restriction/stenosis causes massive lung vascular, perivascular and interstitial fibrosis, massive lung leukocyte infiltration, and effector memory T cells. By using the chimeric mice created by transplantation of Bone Marrow Derived Cells (BMDCs) from GFP mice into wild type mice, we demonstrated that BMDCs contribute to the increased lung myofibroblasts and lung fibrosis, and infiltrated leukocytes. Moreover, we demonstrated that inhibition of lung inflammation by induction of endogenous Tregs or inhibition of T cell activation is effective in attenuating aortic restriction-induced lung fibrosis and inflammation. Finally, we demonstrated that chronic valve diseases or systolic hypertension causes lung consolidation in patients.
Together, our study demonstrated that class-2 PH after aortic stenosis causes lung fibrosis and lung dysfunction, and inhibition of inflammation is effective in attenuating above pathologic process.