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Metabolic Acidosis Inhibits Pulmonary Inflammation and Ameliorates Experimental Pulmonary Hypertension
Author(s) -
Hudalla Hannes,
Michael Zoe,
Kourembanas Stella,
Christou Helen
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.1016.19
Subject(s) - pulmonary hypertension , right ventricular hypertrophy , hypoxia (environmental) , medicine , acetazolamide , pulmonary artery , lung , respiratory acidosis , inflammation , acidosis , pathogenesis , metabolic acidosis , respiratory system , endocrinology , cardiology , pathology , gastroenterology , pharmacology , chemistry , oxygen , organic chemistry
Pulmonary inflammation contributes to the pathogenesis of pulmonary hypertension (PH). We previously reported that metabolic acidosis ameliorated experimental PH but the underlying mechanisms of protection are unknown. We hypothesized that treatment with Acetazolamide (ACTZ) or ammonium chloride (NH 4 Cl) may ameliorate Sugen/Hypoxia (SU/Hx)‐induced severe PH by modulating lung inflammation. Methods Male Sprague‐Dawley rats injected with Sugen (20 mg/kg,sc) or vehicle were exposed to normoxia or hypoxia (9%O 2 ) for 3 weeks. As an early intervention, ACTZ (1.7mg/ml) or NH 4 Cl (1.5%) in the drinking water was given from week 1 to 3 (2 weeks). We assessed hemodynamics and right ventricular hypertrophy (RVH) (Fulton's Index, FI). Lungs, alveolar macrophages, pulmonary arteries (PA) and blood serum were collected for RT‐qPCR and ELISA. Pulmonary artery smooth muscle cells (PASMC) were treated with TNFα (10ng/ml) and de‐differentiation and proliferation was assessed by RT‐qPCR and proliferation assay. Bone marrow‐derived macrophages (BMDM) were polarized to M1 using LPS (100ng/ml) and INF‐γ (20ng/ml) for 6 or 24h and exposed to non‐hypercapnic acidosis at different pH (7.4, 7.0, 6.8) in vitro . Statistical analysis by ANOVA and Mean ±SEM values are presented. Results Both ACTZ‐ and NH 4 Cl‐treatment caused robust metabolic acidosis and significantly lowered RVSP and FI compared to untreated SU/Hx animals (RVSP: 42.47±2.95 vs ACTZ:27.81±2.97 or NH 4 Cl:28.61±1.23 mmHg, FI: 0.66±0.03 vs ACTZ:0.44±0.02 or NH 4 Cl:0.29±0.05). Expression of TNFα, IL‐6, and MCP‐1 of SU/Hx rats were significantly higher in whole lungs and alveolar macrophages from untreated SU/Hx rats compared to controls and serum levels of IL‐6 were also elevated. These changes were ameliorated in the two intervention groups. RT‐qPCR of pulmonary arteries revealed enhanced proliferation and de‐differentiation in untreated SU/Hx animals, and reversal in both intervention groups. In vitro we could demonstrate similar de‐differentiation and proliferation of PASMC upon TNFα treatment. In cultured BMDM, metabolic acidosis down regulated cytokine production (TNFα, IL‐6, and MCP‐1) in a pH‐dependent manner. Conclusion Metabolic acidosis induced by ACTZ or NH 4 Cl ameliorates PH and RVH in the SU/Hx model of severe PH and reduces the lung inflammatory response. pH dependency of cytokine production in macrophages may be a novel therapeutic approach in PH‐related inflammation. Support or Funding Information Funding: NIH 1R01 HL 116573 (to H.C.)