Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome
Abstract
:1. Introduction
2. RAS and Pulmonary Diseases
3. Regulatory, Rather than Harmful or Protective
4. ACE2: Conductor of Inflammatory Response in the Lungs
5. Interactions with Infectious Agents
6. Pharmacological Inhibition of ACE and AT1R in Pulmonary Diseases
7. ACEIs and ARBs in COVID-19
8. Other Non-Classical RAS Components
9. Perspectives for Drug Development
10. Conclusions
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- First, the roles of membrane-bound and soluble ACE2 in the respiratory tract as well as the biological significance of ACE2-shedding under physiological and pathological conditions should be elucidated.
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- The interaction mechanisms of particular infectious agents with the RAS, especially ACE2, are of importance for specific therapeutic approaches.
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- Besides ACE2, other non-classical components of the RAS could also play a significant role in the pathogenesis of acute lung injury and ARDS.
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- The biological impact of established RAS modulating therapies (ACEIs or ARBs) on RAS molecules should be disclosed in ongoing clinical trials.
Author Contributions
Funding
Conflicts of Interest
Abbreviations
α-SMA | α-smooth muscle actin |
ACE | angiotensin converting enzyme |
ACEIs | angiotensin converting enzyme inhibitors |
Ac-SDKP | N-acetyl-seryl-aspartyl-lysyl-proline |
ADAM17 | tumor necrosis factor-α-converting enzyme (TACE) |
ALI | acute lung injury |
Ang | angiotensin |
APA | aminopeptidase A |
APM | aminopeptidase M |
ARBs | angiotensin II type 1 receptor blockers |
ARDS | acute respiratory distress syndrome |
AT1R | angiotensin II type 1 receptor |
AT2R | angiotensin II type 2 receptor |
BAL | bronchoalveolar lavage |
BLM | bleomycin |
CATA | cathepsin A |
CINC-3 | cytokine-induced neutrophil chemoattractant 3 |
COPD | chronic obstructive pulmonary disease |
CxA | carboxypeptidase A |
CXCL5 | C-X-C motif chemokine 5 |
DABK | des-Arg9-bradykinin |
DOCA | deoxycorticosterone acetate |
FiO2 | fraction of inspired oxygen |
GM-CSF | granulocyte-macrophage colony-stimulating factor |
HD | high dose |
ICU | intensive care unit |
IL | interleukin |
i.p. | intraperitoneally |
i.v. | intravenously |
KC | C-X-C motif chemokine 1 |
LD | low dose |
LPS | lipopolysaccharide |
mACE2 | membrane-bound angiotensin converting enzyme 2 |
MasR | Mas receptor |
MCP-1 | monocyte chemoattractant protein-1 |
MIP2 | macrophage inflammatory protein-2 |
MLDAD | mononuclear leukocyte-derived aspartate decarboxylase |
MrgD | Mas-Related G-Protein Coupled Receptor D |
NEP | neprilysin |
PaCO2 | partial pressure of carbon dioxide |
PaO2 | partial pressure of oxygen |
POP | propyl oligopeptidase |
PKC-δ | protein kinase C-δ |
RAS | renin–angiotensin system |
rhACE2 | recombinant human angiotensin converting enzyme 2 |
sACE2 | soluble angiotensin converting enzyme 2 |
s.c. | subcutaneously |
T2D | type 2 diabetes mellitus |
TACE | tumor necrosis factor-α-converting enzyme (ADAM17) |
TGF-β1 | transforming growth factor β1 |
TLR | toll like receptor |
TMPRSS2 | transmembrane protease serine 2 |
TNF-α | tumor necrosis factor-α |
WBC | white blood cells |
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Study Design | Subjects | Outcome | Ref. |
---|---|---|---|
Retrospective cohort study | 254,485 patients > 65 y.o. newly prescribed antihypertensive drugs | ↓ risk of hospitalization with pneumonia within 90 days following treatment initiation with ACEIs/ARBs vs. other antihypertensive drugs | [74] |
Retrospective nested case–control study | 375 COPD patients | ↓ risk of pneumonia | [75] |
Retrospective comparative study | 12,452 patients newly prescribed ACEIs/ARBs within 90 days after diagnosis of COPD | ↓ risk of pneumonia, severe pneumonia and ↓ mortality in ARBs group vs. ACEIs | [76] |
Retrospective cohort study | 215,225 patients | Improved infectious (influenza, pneumonia), inflammatory (COPD) and structural outcomes in ACEIs/ARBs vs. other treatment | [77] |
Retrospective case–control study | 182 ARDS patients | ↑ duration of mechanical ventilation and ICU stay in ACEIs/ARBs group ↑ survival in ACEIs/ARBs group | [78] |
Cox regression longitudinal observational study | 1482 T2D patients | ↓ risk of pneumonia/influenza | [79] |
Treatment | Experimental Model | Effect of Treatment | Ref. |
---|---|---|---|
Ang 1–7 LD: 0.27 μg/kg/h i.v. HD: 60 μg/kg/h i.v. Late-ARDS-study: 300 μg/kg/d i.v. | Sprague Dawley rats HCl- and ventilation-induced injury Late-ARDS- study: 2 weeks post-injury | Improved oxygenation (PaO2/FiO2) ↓ WBC in peripheral blood Late-ARDS: ↓ hydroxyproline content in lung HD: ↓ inflammatory cells in BAL | [36] |
Ang 1–7 2.4 µg/kg/h i.v. | Sprague Dawley rats LPS- and ventilation-induced ARDS | ↑ PaO2 ↑ACE2 and Ang 1–7 in BAL Normalized Ang-(1–7)/Ang II ratio$ ↓ CINC-3, TNF-α, GM-CSF in BAL | [115] |
Ang-1–7 600 μg/kg/d i.p. | Sprague Dawley rats LPS-induced early pulmonary fibrosis | ↓ lung injury and lung fibrose scores ↓ TGF-β in plasma ↓ Ang II in BAL Normalized E-cadherin and vimentin levels in lung ↓ AT1R mRNA expression in lung ↓ cell-membrane AT1R and ↑ MasR in lung ↓ LPS-induced phosphorylation of Src kinase | [30] |
Ang 1–7 100 ng/kg/min s.c. | C57BL/6 mice LPS-induced ALI | ↓ edema, bleeding, collagen and septal widening in lung ↓ TGF-β and p-SMAD2/3 in lung | [119] |
ACE2 2 mg/kg i.p. | C57BL6 mice BLM-induced ALI | ↑ survival, exercise capacity, lung function (dynamic compliance and elastance) ↓ collagen, α-SMA, TGF-β1, TNF- α in lung | [34] |
ACE2 1.0 mg/kg i.v. | C57BL/6 mice LPS-induced ALI | ↓ lung W/D ↓ PaCO2 and ↑ PaO2 ↓ lung histological score ↓ IL-1β, IL-6 and TNF-α in lung and in serum ↓ protein concentration and neutrophil count in BAL ↓ LPS-activated TLR4-signaling | [35] |
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Hrenak, J.; Simko, F. Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome. Int. J. Mol. Sci. 2020, 21, 8038. https://doi.org/10.3390/ijms21218038
Hrenak J, Simko F. Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome. International Journal of Molecular Sciences. 2020; 21(21):8038. https://doi.org/10.3390/ijms21218038
Chicago/Turabian StyleHrenak, Jaroslav, and Fedor Simko. 2020. "Renin–Angiotensin System: An Important Player in the Pathogenesis of Acute Respiratory Distress Syndrome" International Journal of Molecular Sciences 21, no. 21: 8038. https://doi.org/10.3390/ijms21218038