Mechanisms of Pulmonary Hypertension in Acute Respiratory Distress Syndrome (ARDS)

Abstract

Background: Acute respiratory distress syndrome (ARDS) is a severe and often fatal disease. The causes that lead to ARDS are multiple and include inhalation of salt water, smoke particles, or as a result of damage caused by respiratory viruses. ARDS can also arise due to systemic complications such as blood transfusions, sepsis, or pancreatitis. Unfortunately, despite a high mortality rate of 40%, there are limited treatment options available for ARDS outside of last resort options such as mechanical ventilation and extracorporeal support strategies.Aim of review: A complication of ARDS is the development of pulmonary hypertension (PH); however, the mechanisms that lead to PH in ARDS are not fully understood. In this review, we summarize the known mechanisms that promote PH in ARDS.Key scientific concepts of review: (1) Provide an overview of acute respiratory distress syndrome; (2) delineate the mechanisms that contribute to the development of PH in ARDS; (3) address the implications of PH in the setting of coronavirus disease 2019 (COVID-19).

The Right Ventricle in COVID-19

“…As previously mentioned, SARS-CoV2 infects cells through the ACE2 receptor, which may result in an ACE1/ACE2 imbalance and lead to increased ATII signaling through the AT1 receptors, with parallel reduction of Angiotensin 1-7, which normally acts on the MAS receptor to oppose the actions of ATII [88]. Unopposed ATII signaling may promote vasoconstriction, vascular inflammation, microvascular thrombosis, and pulmonary vascular remodeling [99]. Interestingly, ACE2 downregulation has been associated with human pulmonary hypertension [100], and in the experimental setting, ACE2 protects from severe acute lung failure in various models of lung inflammation [101].…”

“…In addition to their effects in promoting thrombotic complications in the lung microcirculation, cytokines, such as IL-6 and TNFα, may also trigger vasoconstriction, both directly and indirectly by suppressing bone morphogenetic receptor 2 signaling in pulmonary vascular smooth muscle cells [99,108]. These cytokines also upregulate the formation of hyaluronan, a component of the extracellular matrix that may represent an important mediator of lung damage in COVID-19 [109] and can promote pulmonary hypertension by fostering stiffness and proliferation of vascular smooth muscle cell [110].…”

Endothelial metabolism in pulmonary vascular homeostasis and acute respiratory distress syndrome

“…It is important to note, however, that patients with COVID-19 on anticoagulants ( 176 ) still developed PH, indicating other factors such as microvascular injury and vasomotor dysregulation may contribute to COVID-19 PH. The renin-angiotensin-aldosterone system (RAAS) is an important regulator of blood pressure and activation of RAAS leads to the release of angiotensin II, a potent vasoconstrictor and mediator of inflammation ( 177 ). Angiotensin II is broken down via the angiotensin converting enzyme 2 (ACE2) which acts as a negative regulator to RAAS ( 177 , 178 ).…”

“…The renin-angiotensin-aldosterone system (RAAS) is an important regulator of blood pressure and activation of RAAS leads to the release of angiotensin II, a potent vasoconstrictor and mediator of inflammation ( 177 ). Angiotensin II is broken down via the angiotensin converting enzyme 2 (ACE2) which acts as a negative regulator to RAAS ( 177 , 178 ). Paradoxically, since ACE2 is also a SARS-CoV-2 receptor, it has been speculated whether chronic downregulation of ACE2 in PAH lungs ( 179 ) protects the PAH population against COVID-19 ( 180 , 181 ).…”

“…Pulmonary vascular injury during the acute phase of COVID-19 can lead to pulmonary artery remodeling, further exacerbating the hypertensive effects with potential long-term consequences ( 177 ). Recently, glycolysis was determined to be a mediator of progressive pulmonary vascular remodeling ( 191 ).…”