Left ventricular failure produces profound lung remodeling and pulmonary hypertension in mice: heart failure causes severe lung disease

Abstract

Chronic left ventricular failure causes pulmonary congestion with increased lung weight and type 2 pulmonary hypertension. Understanding the molecular mechanisms for type 2 pulmonary hypertension and the development of novel treatments for this condition requires a robust experimental animal model and a good understanding of the nature of the resultant pulmonary remodeling. Here we demonstrate that chronic transverse aortic constriction causes massive pulmonary fibrosis and remodeling, as well as type 2 pulmonary hypertension, in mice. Thus, aortic constriction-induced left ventricular dysfunction and increased left ventricular end-diastolic pressure are associated with a ≤5.3-fold increase in lung wet weight and dry weight, pulmonary hypertension, and right ventricular hypertrophy. Interestingly, the aortic constriction-induced increase in lung weight was not associated with pulmonary edema but resulted from profound pulmonary remodeling with a dramatic increase in the percentage of fully muscularized lung vessels, marked vascular and lung fibrosis, myofibroblast proliferation, and leukocyte infiltration. The aortic constriction-induced left ventricular dysfunction was also associated with right ventricular hypertrophy, increased right ventricular end-diastolic pressure, and right atrial hypertrophy. The massive lung fibrosis, leukocyte infiltration, and pulmonary hypertension in mice after transverse aortic constriction clearly indicate that congestive heart failure also causes severe lung disease. The lung fibrosis and leukocyte infiltration may be important mechanisms in the poor clinical outcome in patients with end-stage heart failure. Thus, the effective treatment of left ventricular failure may require additional efforts to reduce lung fibrosis and the inflammatory response.

Figure 1. The TAC-induced increases of lung weight and RV hypertrophy are related to the degree of LV hypertrophy and failure

(A–D) Correlations between LV weight and LA weight, lung weight, RV weight or LV ejection fraction; (E–G) Correlations between LV ejection fraction and LA weight, lung weight , or RV weight; (H) correlation between increase of lung weight and RV weight.

Figure 2. Alterations of heart and lung anatomic data and cardiac function in four experimental groups

(A) LV ejection fraction in each group; (B) Relative LV hypertrophy, (C) LA hypertrophy, (D) increase of lung weight, (E) RV hypertrophy, and (F) RA hypertrophy; (G) HF group shows reduced LV systolic pressure as compared with M-HF group; (H) HF group shows increased LV end-diastolic pressure as compared with other groups; (I,J) HF group shows reduced LV contractility; (K) M-HF and HF groups show increased end-diastolic RV pressure, and (L) increased RV systolic pressure. *p<0.05 vs control group; #p<0.05 vs. corresponding M-HF group.

Figure 3. Chronic TAC and hypoxia cause no pulmonary edema, but cause pulmonary vascular remodeling

(A) Chronic TAC-induced increase of lung weight is not related to pulmonary edema or water retention; (B) Distribution of nonmuscular, partially muscular, and fully muscularized small arteries in mice after chronic hypoxia or TAC-induced M-HF and TAC-induced HF. *p<0.05 vs control group; #p<0.05 vs. corresponding M-HF group.

Figure 4. TAC-induced HF causes massive lung fibrosis in mice

Masson's Trichrome staining was used to show the relative collagen deposition (the blue staining) in lung tissues from control (A), M-HF (B) and HF mice (C–K). (B) The general lung structure of M-HF mice is not dramatically changed, but collagen deposition is increased. (C–K) show prominent lung vascular or perivascular fibrosis, and severe focal fibrosis in collapsed lung tissues in HF mice.

Figure 5. TAC-induced HF causes diffuse lung leukocyte infiltration in mice

(A) Masson's Trichrome staining shows impressive leukocyte infiltration in lung tissues from HF mice compared to controls. (B) The increased infiltration of macrophages was confirmed by staining with macrophage specific marker Mac-2, and (C) the infiltration of neutrophils was confirmed using an antibody specific for neutrophil clone 7/4.

Figure 6. Chronic TAC and hypoxia increased expression of genes related to lung fibrosis and inflammation

(A,B) Expression of TGF-1β; (A,C) Collagen-I; (A,D) collagen-III; (A,E) TNFα; and (A,F,G) adhesion molecules ICAM and VECAM in lung tissues from control group, TAC-induced M-HF or HF groups. (H) The diagram shows the potential mechanism of TAC-induced pulmonary remodeling, pulmonary hypertension and mortality. *p<0.05 vs control group; #p<0.05 vs. corresponding M-HF group.