Impairment of hypoxic pulmonary vasoconstriction in acute respiratory distress syndrome

Mareike Gierhardt, Oleg Pak, Dieter Walmrath, Werner Seeger, Friedrich Grimminger, Hossein A Ghofrani, Norbert Weissmann, Matthias Hecker, Natascha Sommer, Mareike Gierhardt, Oleg Pak, Dieter Walmrath, Werner Seeger, Friedrich Grimminger, Hossein A Ghofrani, Norbert Weissmann, Matthias Hecker, Natascha Sommer

Abstract

Acute respiratory distress syndrome (ARDS) is a serious complication of severe systemic or local pulmonary inflammation, such as caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. ARDS is characterised by diffuse alveolar damage that leads to protein-rich pulmonary oedema, local alveolar hypoventilation and atelectasis. Inadequate perfusion of these areas is the main cause of hypoxaemia in ARDS. High perfusion in relation to ventilation (V/Q<1) and shunting (V/Q=0) is not only caused by impaired hypoxic pulmonary vasoconstriction but also redistribution of perfusion from obstructed lung vessels. Rebalancing the pulmonary vascular tone is a therapeutic challenge. Previous clinical trials on inhaled vasodilators (nitric oxide and prostacyclin) to enhance perfusion to high V/Q areas showed beneficial effects on hypoxaemia but not on mortality. However, specific patient populations with pulmonary hypertension may profit from treatment with inhaled vasodilators. Novel treatment targets to decrease perfusion in low V/Q areas include epoxyeicosatrienoic acids and specific leukotriene receptors. Still, lung protective ventilation and prone positioning are the best available standard of care. This review focuses on disturbed perfusion in ARDS and aims to provide basic scientists and clinicians with an overview of the vascular alterations and mechanisms of V/Q mismatch, current therapeutic strategies, and experimental approaches.

Conflict of interest statement

Conflict of interest: M. Gierhardt has nothing to disclose. Conflict of interest: O. Pak has nothing to disclose. Conflict of interest: D. Walmrath has nothing to disclose. Conflict of interest: W. Seeger reports personal fees from Actelion, Bayer AG, Abivax, Vectura, Medspray, United Therapeutics and Liquidia, outside the submitted work. Conflict of interest: F. Grimminger has nothing to disclose. Conflict of interest: H.A. Ghofrani has nothing to disclose. Conflict of interest: N. Weissmann has nothing to disclose. Conflict of interest: M. Hecker has nothing to disclose. Conflict of interest: N. Sommer has nothing to disclose.

Copyright ©The authors 2021.

Figures

FIGURE 1
FIGURE 1
Mechanism of ventilation/perfusion (V/Q) mismatch in acute respiratory distress syndrome (ARDS). a) ARDS is characterised by diffuse alveolar damage leading to oedema and atelectasis. The computed tomography scan performed in supine position of the patient demonstrates bilateral dense consolidations (*) in the most dependent region and normal attenuation in the non-dependent region of the lung. b) In healthy lungs alveolar hypoxia (e.g. due to hypoventilation) leads to hypoxic pulmonary vasoconstriction (HPV) of precapillary vessels matching the perfusion (Q) to regional ventilation (V) and thus optimising arterial oxygenation. c) In ARDS a disbalance of vasoconstriction in well ventilated areas and vasodilation in poorly ventilated areas (due to inhibition of HPV) results in blood flow redistribution from well to poorly ventilated alveoli and a V/Q mismatch leading to hypoxaemia. Further factors contributing to low perfusion of well-ventilated alveoli are vascular obstruction by oedema, infiltration, and (micro)thrombosis. In the schematic, the size of vessels indicates amount of blood flow. CO: cardiac output; PvO2: mixed venous partial pressure of O2.
FIGURE 2
FIGURE 2
Trigger mechanisms, modulation and acute respiratory distress syndrome (ARDS)-related dysregulation of hypoxic pulmonary vasoconstriction (HPV). a) Primary mechanisms underlying HPV include oxygen sensing by mitochondria with a subsequent change in cellular redox state and/or release of reactive oxygen species that interact with various plasma membrane ion channels to trigger a cytosolic calcium increase and HPV. Other mechanisms which may contribute to HPV include a change in intracellular AMP/ATP levels, activation of phospholipase C, increasing diacylglycerol levels and propagation of endothelial signals by gap junctions and sphingosine-1-phosphate signalling. During prolonged hypoxia, further mechanisms such as increased calcium sensitisation by Rho-kinase may come into play. Dashed lines/symbols indicate hypothetical pathways. b) HPV is modulated by the endothelium through factors involving nitric oxide (NO)–soluble guanylyl cyclase–cyclic guanosine monophosphate signalling, arachidonic acid-derived vasoactive factors (such as prostacyclin (PGI2), thromboxane A2 (TXA2) and epoxyeicosatrienoic acids (EETs)), angiotensin II (ATII) and endothelin-1 (ET-1), prompting vasodilation or vasoconstriction. Leukotrienes have direct effects on the smooth muscle cell but mainly act in ARDS via promoting inflammation. In ARDS, a locally high increase of NO, PGI2 and decrease of EET may inhibit HPV and cause low ventilation/perfusion (V/Q) areas. In contrast, an increase of the vasoconstrictive substances ATII, ET-1 and TXA2 in the pulmonary circulation causes vasoconstriction thereby promoting V/Q mismatch and pulmonary hypertension. Alterations in the levels of the different vasoactive substances in ARDS are given in red arrows, with the arrows in brackets when only data for animal studies are available. Therapeutic approaches that were/are tested in clinical trials are given in green. Please note that inhaled NO and prostacyclines enhance vasodilation only in ventilated lung areas. Thereby they improve V/Q matching in 1) high V/Q areas and 2) low V/Q areas by decreasing redistribution of blood flow. For detailed information please refer to text. AA: arachidonic acid; AGTR1: angiotensin receptor 1; ACE: angiotensin converting enzyme; AMP: adenosine monophosphate; AT: angiotensin; ATP: adenosine triphosphase; AMPK: 5′ AMP-activated protein kinase; BLT1: leukotriene B4 receptor 1; CFTR: cystic fibrosis transmembrane conductance regulator; COX: cyclooxygenase; Cox4i2: cytochrome C oxidase subunit 4I2; CYP450: cytochrome P450; CysLTs: cysteinyl leukotrienes; CysLTR1: cysteinyl leukotriene receptor 1; Cx40: connexin 40; DAG: diacylglycerol; ΔEm: membrane potential; EC: endothelial cell; IP: prostaglandin I2 receptor; GJ: gap junctions; (c)GMP: (cyclic) guanosine monophosphate; GSSG/GSH: redox state of glutathione; GTP: guanosine triphosphate; Kv: voltage-dependent potassium; 5-LOX: 5-lipoxygenase; LTB4: leukotriene B4; NAD/NADH: redox state of nicotinamide adenine dinucleotide; (i)NO: (inhaled) nitric oxide; (i)NOS: (inducible) nitric oxide synthase; PASMC: pulmonary artery smooth muscle cell; PDE5: phosphodiesterase 5; PLA2: phospholipase A2; PLC: phospholipase C; rhACE2: recombinant human angiotensin converting enzyme 2; ROCK: rho-associated kinase; S1P: sphingosine-1-phosphate; sEH: soluble epoxide hydrolase; sGC: soluble guanylyl cyclase; SphK1: sphingosinekinase 1; TP: T prostanoid receptor; TRPC6: transient receptor potential canonical channel type 6; TRPV4: transient receptor potential vanilloid 4; VDCC: voltage-dependent calcium channel; V/Q: ratio of alveolar ventilation to perfusion.
FIGURE 3
FIGURE 3
Schematic overview of therapeutic interventions addressing ventilation/perfusion (V/Q) mismatch. a) Prone positioning: in contrast to supine positioning (ai), prone positioning (aii) leads to recruitment of previously atelectatic dorsal lung areas for ventilation while the ventral lung areas become less ventilated. Promoted by gravitational distribution of blood flow, the large dorsal lung areas will show improved V/Q matching with V/Q ratios up to one, while V/Q matching in the smaller ventral lung will be impaired. b) Positive end-expiratory pressure (PEEP) ventilation: beside gravitation, vascular obstruction, redistribution of blood flow to poorly ventilated areas, and impaired hypoxic pulmonary vasoconstriction can lead to V/Q mismatch in acute respiratory distress syndrome (ARDS) (bi). PEEP ventilation (bii) can improve V/Q mismatch by opening atelectasis. However, at the same time it may cause hyperinflation of previously well-ventilated alveoli, and thereby 1) restrict perfusion in these areas causing areas of a high V/Q ratio and 2) cause redistribution of perfusion to less ventilated dependent lung regions. In the schematic, the size of vessels indicates amount of blood flow. For detailed information please refer to main text. CO: cardiac output; PVO2: mixed venous partial pressure of O2.

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