PMID- 30951642
OWN - NLM
STAT- MEDLINE
DCOM- 20200504
LR  - 20240408
IS  - 1535-4989 (Electronic)
IS  - 1044-1549 (Print)
IS  - 1044-1549 (Linking)
VI  - 61
IP  - 4
DP  - 2019 Oct
TI  - Carbonic Anhydrase Inhibition Ameliorates Inflammation and Experimental Pulmonary 
      Hypertension.
PG  - 512-524
LID - 10.1165/rcmb.2018-0232OC [doi]
AB  - Inflammation and vascular smooth muscle cell (VSMC) phenotypic switching are 
      causally linked to pulmonary arterial hypertension (PAH) pathogenesis. Carbonic 
      anhydrase inhibition induces mild metabolic acidosis and exerts protective 
      effects in hypoxic pulmonary hypertension. Carbonic anhydrases and metabolic 
      acidosis are further known to modulate immune cell activation. To evaluate if 
      carbonic anhydrase inhibition modulates macrophage activation, inflammation, and 
      VSMC phenotypic switching in severe experimental pulmonary hypertension, 
      pulmonary hypertension was assessed in Sugen 5416/hypoxia (SU/Hx) rats after 
      treatment with acetazolamide or ammonium chloride (NH(4)Cl). We evaluated 
      pulmonary and systemic inflammation and characterized the effect of carbonic 
      anhydrase inhibition and metabolic acidosis in alveolar macrophages and bone 
      marrow-derived macrophages (BMDMs). We further evaluated the treatment effects on 
      VSMC phenotypic switching in pulmonary arteries and pulmonary artery smooth 
      muscle cells (PASMCs) and corroborated some of our findings in lungs and 
      pulmonary arteries of patients with PAH. Both patients with idiopathic PAH and 
      SU/Hx rats had increased expression of lung inflammatory markers and signs of 
      PASMC dedifferentiation in pulmonary arteries. Acetazolamide and NH(4)Cl 
      ameliorated SU/Hx-induced pulmonary hypertension and blunted pulmonary and 
      systemic inflammation. Expression of carbonic anhydrase isoform 2 was increased 
      in alveolar macrophages from SU/Hx animals, classically (M1) and alternatively 
      (M2) activated BMDMs, and lungs of patients with PAH. Carbonic anhydrase 
      inhibition and acidosis had distinct effects on M1 and M2 markers in BMDMs. 
      Inflammatory cytokines drove PASMC dedifferentiation, and this was inhibited by 
      acetazolamide and acidosis. The protective antiinflammatory effect of 
      acetazolamide in pulmonary hypertension is mediated by a dual mechanism of 
      macrophage carbonic anhydrase inhibition and systemic metabolic acidosis.
FAU - Hudalla, Hannes
AU  - Hudalla H
AD  - Department of Pediatric Newborn Medicine and.
AD  - Department of Neonatology, Heidelberg University Children's Hospital, Heidelberg, 
      Germany.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Michael, Zoe
AU  - Michael Z
AD  - Department of Pediatric Newborn Medicine and.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Christodoulou, Nicolas
AU  - Christodoulou N
AD  - Department of Pediatric Newborn Medicine and.
FAU - Willis, Gareth R
AU  - Willis GR
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; 
      and.
FAU - Fernandez-Gonzalez, Angeles
AU  - Fernandez-Gonzalez A
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; 
      and.
FAU - Filatava, Evgenia J
AU  - Filatava EJ
AD  - Department of Pediatric Newborn Medicine and.
FAU - Dieffenbach, Paul
AU  - Dieffenbach P
AD  - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 
      Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Fredenburgh, Laura E
AU  - Fredenburgh LE
AD  - Division of Pulmonary and Critical Care Medicine, Brigham and Women's Hospital, 
      Boston, Massachusetts.
AD  - Harvard Medical School, Boston, Massachusetts.
FAU - Stearman, Robert S
AU  - Stearman RS
AD  - Division of Pulmonary, Critical Care Medicine, Sleep, and Occupational Medicine, 
      Department of Medicine, School of Medicine, Indiana University, Indianapolis, 
      Indiana.
FAU - Geraci, Mark W
AU  - Geraci MW
AD  - Division of Pulmonary, Critical Care Medicine, Sleep, and Occupational Medicine, 
      Department of Medicine, School of Medicine, Indiana University, Indianapolis, 
      Indiana.
FAU - Kourembanas, Stella
AU  - Kourembanas S
AD  - Department of Pediatric Newborn Medicine and.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; 
      and.
FAU - Christou, Helen
AU  - Christou H
AD  - Department of Pediatric Newborn Medicine and.
AD  - Harvard Medical School, Boston, Massachusetts.
AD  - Division of Newborn Medicine, Boston Children's Hospital, Boston, Massachusetts; 
      and.
LA  - eng
GR  - R01 HL114839/HL/NHLBI NIH HHS/United States
GR  - P30 HD018655/HD/NICHD NIH HHS/United States
GR  - R01 HL116573/HL/NHLBI NIH HHS/United States
GR  - R24 HL123767/HL/NHLBI NIH HHS/United States
GR  - R01 HL137366/HL/NHLBI NIH HHS/United States
GR  - F32 HL131228/HL/NHLBI NIH HHS/United States
GR  - R01 HL055454/HL/NHLBI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PL  - United States
TA  - Am J Respir Cell Mol Biol
JT  - American journal of respiratory cell and molecular biology
JID - 8917225
RN  - 0 (Carbonic Anhydrase Inhibitors)
RN  - 0 (Contractile Proteins)
RN  - 0 (Protein Isoforms)
RN  - 0 (RNA, Messenger)
RN  - 01Q9PC255D (Ammonium Chloride)
RN  - EC 4.2.1.1 (Carbonic Anhydrases)
RN  - O3FX965V0I (Acetazolamide)
SB  - IM
CIN - Am J Respir Cell Mol Biol. 2019 Oct;61(4):412-413. PMID: 30973760
MH  - Acetazolamide/*therapeutic use
MH  - Acidosis/chemically induced/complications/immunology
MH  - Ammonium Chloride/*therapeutic use
MH  - Animals
MH  - Carbonic Anhydrase Inhibitors/*therapeutic use
MH  - Carbonic Anhydrases/*physiology
MH  - Cell Differentiation/drug effects
MH  - Contractile Proteins/biosynthesis/genetics
MH  - Drug Evaluation, Preclinical
MH  - Humans
MH  - Hypertension, Pulmonary/*drug therapy/enzymology/etiology/pathology
MH  - Hypoxia/complications
MH  - Inflammation
MH  - Macrophages/drug effects/enzymology
MH  - Macrophages, Alveolar/drug effects/enzymology
MH  - Male
MH  - Muscle, Smooth, Vascular/pathology
MH  - Myocytes, Smooth Muscle/drug effects/enzymology
MH  - Protein Isoforms/antagonists & inhibitors
MH  - Pulmonary Artery/pathology
MH  - RNA, Messenger/biosynthesis/genetics
MH  - Rats
MH  - Rats, Sprague-Dawley
PMC - PMC6775956
OTO - NOTNLM
OT  - acetazolamide
OT  - acidosis
OT  - carbonic anhydrases
OT  - lung
OT  - macrophages
EDAT- 2019/04/06 06:00
MHDA- 2020/05/06 06:00
PMCR- 2020/10/01
CRDT- 2019/04/06 06:00
PHST- 2019/04/06 06:00 [pubmed]
PHST- 2020/05/06 06:00 [medline]
PHST- 2019/04/06 06:00 [entrez]
PHST- 2020/10/01 00:00 [pmc-release]
AID - 10.1165/rcmb.2018-0232OC [doi]
PST - ppublish
SO  - Am J Respir Cell Mol Biol. 2019 Oct;61(4):512-524. doi: 10.1165/rcmb.2018-0232OC.