Pulmonary Vascular Responses to Chronic Intermittent Hypoxia in a Guinea Pig Model of Obstructive Sleep Apnea.

Experimental evidence suggests that chronic intermittent hypoxia (CIH), a major hallmark of obstructive sleep apnea (OSA), boosts carotid body (CB) responsiveness, thereby causing increased sympathetic activity, arterial and pulmonary hypertension, and cardiovascular disease. An enhanced circulatory chemoreflex, oxidative stress, and NO signaling appear to play important roles in these responses to CIH in rodents. Since the guinea pig has a hypofunctional CB (i.e., it is a natural CB knockout), in this study we used it as a model to investigate the CB dependence of the effects of CIH on pulmonary vascular responses, including those mediated by NO, by comparing them with those previously described in the rat. We have analyzed pulmonary artery pressure (PAP), the hypoxic pulmonary vasoconstriction (HPV) response, endothelial function both in vivo and in vitro, and vascular remodeling (intima-media thickness, collagen fiber content, and vessel lumen area). We demonstrate that 30 days of the exposure of guinea pigs to CIH (FiO2, 5% for 40 s, 30 cycles/h) induces pulmonary artery remodeling but does not alter endothelial function or the contractile response to phenylephrine (PE) in these arteries. In contrast, CIH exposure increased the systemic arterial pressure and enhanced the contractile response to PE while decreasing endothelium-dependent vasorelaxation to carbachol in the aorta without causing its remodeling. We conclude that since all of these effects are independent of CB sensitization, there must be other oxygen sensors, beyond the CB, with the capacity to alter the autonomic control of the heart and vascular function and structure in CIH.

[Effects of Rhodiola rosea injection on intrapulmonary shunt and blood IL-6 and TNF-α levels during single lung ventilation in patients undergoing radical resection of esophageal cancer].

OBJECTIVE: To explore the effects of Rhodiola rosea injection on pulmonary shunt and serum interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α) levels during single lung ventilation in patients undergoing radical resection of esophageal cancer. METHODS: Forty-six patients undergoing radical operation for esophageal cancer were randomized equally into control group and Rhodiola rosea injection group. In the Rhodiola group, 10 mL of Rhodiola rosea injection was added into 250 mL of normal saline or 5% glucose solution for slow intravenous infusion, and normal saline of the same volume was used in the control group after the patients entered the operation room. At T0, T1 and T3, PaO2 of the patient was recorded and 2 mL of deep venous blood was collected for determination of serum TNF-α and IL-6 levels. The incidence of postoperative atelectasis of the patients was recorded. RESULTS: Compared with those in the control group, the patients receiving Rhodiola rosea injection had significantly higher PaO2 and Qs/Qt at T1 and T2 (P<0.05) and lower serum IL-6 and TNF-α levels at T3 (P<0.05). No significant difference in the incidence of postoperative atelectasis was observed between the two groups (P>0.05). CONCLUSION: Rhodiola rosea injection before anesthesia induction can reduce intrapulmonary shunt during single lung ventilation, improve oxygenation, reduce serum IL-6 and TNF-α levels, and alleviate intraoperative lung injury in patients undergoing radical resection of esophageal cancer.

Hypoxia in the pulmonary vein increases pulmonary vascular resistance independently of oxygen in the pulmonary artery.

INTRODUCTION: Hypoxic pulmonary vasoconstriction (HPV) can be a challenging clinical problem. It is not fully elucidated where in the circulation the regulation of resistance takes place. It is often referred to as if it is in the arteries, but we hypothesized that it is in the venous side of the pulmonary circulation. METHODS: In an open thorax model, pigs were treated with a veno-venous extra corporeal membrane oxygenator to either oxygenate or deoxygenate blood passing through the pulmonary vessels. At the same time the lungs were ventilated with extreme variations of inspired air from 5% to 100% oxygen, making it possible to make combinations of high and low oxygen content through the pulmonary circulation. A flow probe was inserted around the main pulmonary artery and catheters in the pulmonary artery and in the left atrium were used for pressure monitoring and blood tests. Under different combinations of oxygenation, pulmonary vascular resistance (PVR) was calculated. RESULTS: With unchanged level of oxygen in the pulmonary artery and reduced inspired oxygen fraction lowering oxygen tension from 29 to 6.7 kPa in the pulmonary vein, PVR was doubled. With more extreme hypoxia PVR suddenly decreased. Combinations with low oxygenation in the pulmonary artery did not systematic influence PVR if there was enough oxygen in the inspired air and in the pulmonary veins. DISCUSSION: The impact of hypoxia occurs from the alveolar level and forward with the blood flow. The experiments indicated that the regulation of PVR is mediated from the venous side.

Assessing the pulmonary vascular responsiveness to oxygen with proton MRI.

Ventilation-perfusion matching occurs passively and is also actively regulated through hypoxic pulmonary vasoconstriction (HPV). The extent of HPV activity in humans, particularly normal subjects, is uncertain. Current evaluation of HPV assesses changes in ventilation-perfusion relationships/pulmonary vascular resistance with hypoxia and is invasive, or unsuitable for patients because of safety concerns. We used a noninvasive imaging-based approach to quantify the pulmonary vascular response to oxygen as a metric of HPV by measuring perfusion changes between breathing 21% and 30%O2 using arterial spin labeling (ASL) MRI. We hypothesized that the differences between 21% and 30%O2 images reflecting HPV release would be 1) significantly greater than the differences without [Formula: see text] changes (e.g., 21-21% and 30-30%O2) and 2) negatively associated with ventilation-perfusion mismatch. Perfusion was quantified in the right lung in normoxia (baseline), after 15 min of 30% O2 breathing (hyperoxia) and 15 min normoxic recovery (recovery) in healthy subjects (7 M, 7 F; age = 41.4 ± 19.6 yr). Normalized, smoothed, and registered pairs of perfusion images were subtracted and the mean square difference (MSD) was calculated. Separately, regional alveolar ventilation and perfusion were quantified from specific ventilation, proton density, and ASL imaging; the spatial variance of ventilation-perfusion (σ2V̇a/Q̇) distributions was calculated. The O2-responsive MSD was reproducible (R2 = 0.94, P < 0.0001) and greater (0.16 ± 0.06, P < 0.0001) than that from subtracted images collected under the same [Formula: see text] (baseline = 0.09 ± 0.04, hyperoxia = 0.08 ± 0.04, recovery = 0.08 ± 0.03), which were not different from one another (P = 0.2). The O2-responsive MSD was correlated with σ2V̇a/Q̇ (R2 = 0.47, P = 0.007). These data suggest that active HPV optimizes ventilation-perfusion matching in normal subjects. This noninvasive approach could be applied to patients with different disease phenotypes to assess HPV and ventilation-perfusion mismatch.NEW & NOTEWORTHY We developed a new proton MRI method to noninvasively quantify the pulmonary vascular response to oxygen. Using a hyperoxic stimulus to release HPV, we quantified the resulting redistribution of perfusion. The differences between normoxic and hyperoxic images were greater than those between images without [Formula: see text] changes and negatively correlated with ventilation-perfusion mismatch. This suggests that active HPV optimizes ventilation-perfusion matching in normal subjects. This approach is suitable for assessing patients with different disease phenotypes.

Hypoxic pulmonary vasoconstriction does not limit maximal exercise capacity in healthy volunteers breathing 12% oxygen at sea level.

Maximal exercise capacity is reduced at altitude or during hypoxia at sea level. It has been suggested that this might reflect increased right ventricular afterload due to hypoxic pulmonary vasoconstriction. We have shown previously that the pulmonary vascular sensitivity to hypoxia is enhanced by sustained isocapnic hypoxia, and inhibited by intravenous iron. In this study, we tested the hypothesis that elevated pulmonary artery pressure contributes to exercise limitation during acute hypoxia. Twelve healthy volunteers performed incremental exercise tests to exhaustion breathing 12% oxygen, before and after sustained (8-h) isocapnic hypoxia at sea level. Intravenous iron sucrose (n = 6) or saline placebo (n = 6) was administered immediately before the sustained hypoxia. In the placebo group, there was a substantial (12.6 ± 1.5 mmHg) rise in systolic pulmonary artery pressure (SPAP) during sustained hypoxia, but no associated fall in maximal exercise capacity breathing 12% oxygen. In the iron group, the rise in SPAP during sustained hypoxia was markedly reduced (3.4 ± 1.0 mmHg). There was a small rise in maximal exercise capacity following sustained hypoxia within the iron group, but no overall effect of iron, compared with saline. These results do not support the hypothesis that elevated SPAP inhibits maximal exercise capacity during acute hypoxia in healthy volunteers.

Pulmonary Hypertension in Established Bronchopulmonary Dysplasia: Physiologic Approaches to Clinical Care.

Preterm infants with bronchopulmonary dysplasia (BPD) are prone to develop pulmonary hypertension (PH). Strong laboratory and clinical data suggest that antenatal factors, such as preeclampsia, chorioamnionitis, oligohydramnios, and placental dysfunction leading to fetal growth restriction, increase susceptibility for BPD-PH after premature birth. Echocardiogram metrics and serial assessments of NT-proBNP provide useful tools to diagnose and monitor clinical course during the management of BPD-PH, as well as monitoring for such complicating conditions as left ventricular diastolic dysfunction, shunt lesions, and pulmonary vein stenosis. Therapeutic strategies should include careful assessment and management of underlying airways and lung disease, cardiac performance, and systemic hemodynamics, prior to initiation of PH-targeted drug therapies.

Hemorheological, cardiorespiratory, and cerebrovascular effects of pentoxifylline following acclimatization to 3,800 m.

Pentoxifylline is a nonselective phosphodiesterase inhibitor used for the treatment of peripheral artery disease. Pentoxifylline acts through cyclic adenosine monophosphate, thereby enhancing red blood cell deformability, causing vasodilation and decreasing inflammation, and potentially stimulating ventilation. We conducted a double-blind, placebo-controlled, crossover, counter-balanced study to test the hypothesis that pentoxifylline could lower blood viscosity, enhance cerebral blood flow, and decrease pulmonary artery pressure in lowlanders following 11-14 days at 3,800 m. Participants (6 males/10 females; age, 27 ± 4 yr old) received either a placebo or 400 mg of pentoxifylline orally the night before and again 2 h before testing. We assessed arterial blood gases, venous hemorheology (blood viscosity, red blood cell deformability, and aggregation), and inflammation (TNF-α) in room air (end-tidal oxygen partial pressure, ∼52 mmHg). Global cerebral blood flow (gCBF), ventilation, and pulmonary artery systolic pressure (PASP) were measured in room air and again after 8-10 min of isocapnic hypoxia (end-tidal oxygen partial pressure, 40 mmHg). Pentoxifylline did not alter arterial blood gases, TNF-α, or hemorheology compared with placebo. Pentoxifylline did not affect gCBF or ventilation during room air or isocapnic hypoxia compared with placebo. However, in females, PASP was reduced with pentoxifylline during room air (placebo, 19 ± 3; pentoxifylline, 16 ± 3 mmHg; P = 0.021) and isocapnic hypoxia (placebo, 22 ± 5; pentoxifylline, 20 ± 4 mmHg; P = 0.029), but not in males. Acute pentoxifylline administration in lowlanders at 3,800 m had no impact on arterial blood gases, hemorheology, inflammation, gCBF, or ventilation. Unexpectedly, however, pentoxifylline reduced PASP in female participants, indicating a potential effect of sex on the pulmonary vascular responses to pentoxifylline.NEW & NOTEWORTHY We conducted a double-blind, placebo-controlled study on the rheological, cardiorespiratory and cerebrovascular effects of acute pentoxifylline in healthy lowlanders after 11-14 days at 3,800 m. Although red blood cell deformability was reduced and blood viscosity increased compared with low altitude, acute pentoxifylline administration had no impact on arterial blood gases, hemorheology, inflammation, cerebral blood flow, or ventilation. Pentoxifylline decreased pulmonary artery systolic pressure in female, but not male, participants.

Magnetic Resonance Imaging of Lung Perfusion.

"Lung perfusion" in the context of imaging conventionally refers to the delivery of blood to the pulmonary capillary bed through the pulmonary arteries originating from the right ventricle required for oxygenation. The most important physiological mechanism in the context of imaging is the so-called hypoxic pulmonary vasoconstriction (HPV, also known as "Euler-Liljestrand-Reflex"), which couples lung perfusion to lung ventilation. In obstructive airway diseases such as asthma, chronic-obstructive pulmonary disease (COPD), cystic fibrosis (CF), and asthma, HPV downregulates pulmonary perfusion in order to redistribute blood flow to functional lung areas in order to conserve optimal oxygenation. Imaging of lung perfusion can be seen as a reflection of lung ventilation in obstructive airway diseases. Other conditions that primarily affect lung perfusion are pulmonary vascular diseases, pulmonary hypertension, or (chronic) pulmonary embolism, which also lead to inhomogeneity in pulmonary capillary blood distribution. Several magnetic resonance imaging (MRI) techniques either dependent on exogenous contrast materials, exploiting periodical lung signal variations with cardiac action, or relying on intrinsic lung voxel attributes have been demonstrated to visualize lung perfusion. Additional post-processing may add temporal information and provide quantitative information related to blood flow. The most widely used and robust technique, dynamic-contrast enhanced MRI, is available in clinical routine assessment of COPD, CF, and pulmonary vascular disease. Non-contrast techniques are important research tools currently requiring clinical validation and cross-correlation in the absence of a viable standard of reference. First data on many of these techniques in the context of observational studies assessing therapy effects have just become available. LEVEL OF EVIDENCE: 5 TECHNICAL EFFICACY: Stage 5.

Oxygen-sensing pathways and the pulmonary circulation.

The unique property of the pulmonary circulation to constrict in response to hypoxia, rather than dilate, brings advantages in both health and disease. Hypoxic pulmonary vasoconstriction (HPV) acts to optimise ventilation-perfusion matching - this is important clinically both in focal disease (such as pneumonia) and in one-lung ventilation during anaesthesia for thoracic surgery. However, during global hypoxia such as that encountered at high altitude, generalised pulmonary vasoconstriction can lead to pulmonary hypertension. There is now a growing body of evidence that links the hypoxia-inducible factor (HIF) pathway and pulmonary vascular tone - in both acute and chronic settings. Genetic and pharmacological alterations to all key components of this pathway (VHL - von Hippel-Lindau ubiquitin E3 ligase; PHD2 - prolyl hydroxylase domain protein 2; HIF1 and HIF2) have clear effects on the pulmonary circulation, particularly in hypoxia. Furthermore, knowledge of the molecular biology of the prolyl hydroxylase enzymes has led to an extensive and ongoing body of research into the importance of iron in both HPV and pulmonary hypertension. This review will explore these relationships in more detail and discuss future avenues of research.

Effects of Zinc on the Right Cardiovascular Circuit in Long-Term Hypobaric Hypoxia in Wistar Rats.

Hypobaric hypoxia under chromic conditions triggers hypoxic pulmonary vasoconstriction (HPV) and right ventricular hypertrophy (RVH). The role of zinc (Zn) under hypoxia is controversial and remains unclear. We evaluated the effect of Zn supplementation in prolonged hypobaric hypoxia on HIF2α/MTF-1/MT/ZIP12/PKCε pathway in the lung and RVH. Wistar rats were exposed to hypobaric hypoxia for 30 days and randomly allocated into three groups: chronic hypoxia (CH); intermittent hypoxia (2 days hypoxia/2 days normoxia; CIH); and normoxia (sea level control; NX). Each group was subdivided (n = 8) to receive either 1% Zn sulfate solution (z) or saline (s) intraperitoneally. Body weight, hemoglobin, and RVH were measured. Zn levels were evaluated in plasma and lung tissue. Additionally, the lipid peroxidation levels, HIF2α/MTF-1/MT/ZIP12/PKCε protein expression and pulmonary artery remodeling were measured in the lung. The CIH and CH groups showed decreased plasma Zn and body weight and increased hemoglobin, RVH, and vascular remodeling; the CH group also showed increased lipid peroxidation. Zn administration under hypobaric hypoxia upregulated the HIF2α/MTF-1/MT/ZIP12/PKCε pathway and increased RVH in the intermittent zinc group. Under intermittent hypobaric hypoxia, Zn dysregulation could participate in RVH development through alterations in the pulmonary HIF2α/MTF1/MT/ZIP12/PKCε pathway.

Effect of Deferasirox on Shunt Fraction During Thoracic Surgery With One-Lung Ventilation: A Randomized Controlled Study.

Context Deferasirox, an iron chelator, can potentially reduce intraoperative right-to-left shunt and improve oxygenation in patients undergoing thoracic surgery requiring one-lung ventilation (OLV) by potentiating hypoxic pulmonary vasoconstriction (HPV). Aim The aim was to determine the effect of deferasirox on the intraoperative shunt fraction (SF) of patients undergoing thoracic surgery using OLV. Study design and settings This was a prospective, single-blind, randomized, controlled study. The study was conducted at a tertiary-care hospital. Methods Before surgery, 64 patients were allocated to two groups comprising 32 patients each. Group D patients were administered deferasirox, while those in group C were given a placebo. We included patients with the American Society of Anesthesiologists physical status III or IV, aged 18-60 years, undergoing elective thoracic surgery needing OLV. SF was the primary outcome variable. Secondary outcome variables were arterial oxygen tension (PaO2), peripheral oxygen saturation (SpO2), the ratio of PaO2 and inspired oxygen concentration (P/F), and complications such as desaturation episodes, hypotension, and tachycardia. Results Baseline and postoperative values of outcome variables were statistically similar in both groups. Intraoperative values of SF were lower and PaO2, SpO2, and P/F were higher in group D. The incidence of intraoperative desaturation was lower in group D. Conclusion We conclude that pre-treatment with deferasirox reduces intraoperative SF and improves oxygenation during thoracic surgery using OLV.

Nicardipine-induced acute respiratory failure: Case report and literature review.

Hypoxic pulmonary vasoconstriction (HPV) is a major physiological mechanism that prevents the development of hypoxemia secondary to a regional decrease in the ventilation-perfusion ratio (the intrapulmonary shunt effect). Calcium plays a critical role in the cellular response to hypoxia and the regulation of the pulmonary vascular tone. Therefore, calcium channel antagonists such as nicardipine have the potential to interfere with the pulmonary response to hypoxia, increasing intrapulmonary blood shunt and thus worsening underlying hypoxemia. This article reports the case of a 40-year-old man suffering from lobar pneumonia, who developed a rapidly progressing hypoxemia after starting nicardipine infusion for blood pressure control. After ruling out all major causes of hypoxemic respiratory failure, the involvement of the calcium channel antagonist was strongly suspected. Hypoxemia caused by HPV release is an underreported side effect of calcium channel blockers. There are few clinical reports that describe the occurrence of this adverse event, and to our knowledge, only one other publication describes a patient suffering from infectious pneumopathy. In this article, we discuss the cellular mechanisms behind the HPV, as well as the pharmacology of calcium channel antagonists and their involvement in the development of acute respiratory failure. The purpose of this report is to remind clinicians dealing with patients affected by acute hypoxemia that pharmacologic HPV inhibition should be considered as part of the differential diagnosis, thus avoiding unnecessary costly and time-consuming assessments.

Left bronchial compression after an arterial switch operation with the LeCompte maneuver for transposition of the great arteries: A case report and literature review.

Left bronchial compression is a rarely reported, postoperative complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries. Postoperative neopulmonary root dilatation and the anterior-posterior, anatomical relationship of the great vessels may cause this condition. Hypoxic pulmonary vasoconstriction may mask the condition even if the left bronchus has been severely obstructed. The apparent inconsistency between the abnormally decreased pulmonary blood flow and the absence of any irregularities in the vascular structure that might account for it suggested hypoxic pulmonary vasoconstriction to be the cause. We present herein a case of left bronchial compression presenting malacia after an arterial switch operation with the LeCompte maneuver and also present a review of seven, other, reported cases. Learning objectives: Left bronchial compression is a rare complication of the arterial switch operation with the LeCompte maneuver for transposition of the great arteries and is possibly caused by root dilatation and the anatomical relationship of the great vessels. Hypoxic pulmonary vasoconstriction may mask the condition.

Imaging Depiction of Hypoxic Pulmonary Vasoconstriction Using Dual-Energy CT.

In this article, we aim to highlight the utility of dual-energy computed tomography (DECT) in demonstrating imaging changes due to hypoxic pulmonary vasoconstriction (HPV). DECT allows detailed image reconstructions that have been shown to better characterize cardiothoracic pathologies, as compared to conventional CT techniques. DECT simultaneously detects two different X-ray energies, which enables generation of iodine density maps, virtual monoenergetic images, and effective atomic number maps (Zeff), among others. DECT has been shown to have utility in the assessment of benign versus malignant pulmonary nodules, pulmonary embolism, myocardial perfusion defects, and other conditions. Herein, we describe four cases of indeterminate pulmonary pathology when imaged with conventional CT in which subsequent use of DECT-derived image reconstructions demonstrated HPV as the underlying pathophysiological mechanism. The goal of this article is to understand the imaging appearance of HPV on DECT and discuss how HPV may mimic other causes of perfusion defects.

Acute oxygen sensing by vascular smooth muscle cells.

An adequate supply of oxygen (O2) is essential for most life forms on earth, making the delivery of appropriate levels of O2 to tissues a fundamental physiological challenge. When O2 levels in the alveoli and/or blood are low, compensatory adaptive reflexes are produced that increase the uptake of O2 and its distribution to tissues within a few seconds. This paper analyzes the most important acute vasomotor responses to lack of O2 (hypoxia): hypoxic pulmonary vasoconstriction (HPV) and hypoxic vasodilation (HVD). HPV affects distal pulmonary (resistance) arteries, with its homeostatic role being to divert blood to well ventilated alveoli to thereby optimize the ventilation/perfusion ratio. HVD is produced in most systemic arteries, in particular in the skeletal muscle, coronary, and cerebral circulations, to increase blood supply to poorly oxygenated tissues. Although vasomotor responses to hypoxia are modulated by endothelial factors and autonomic innervation, it is well established that arterial smooth muscle cells contain an acute O2 sensing system capable of detecting changes in O2 tension and to signal membrane ion channels, which in turn regulate cytosolic Ca2+ levels and myocyte contraction. Here, we summarize current knowledge on the nature of O2 sensing and signaling systems underlying acute vasomotor responses to hypoxia. We also discuss similarities and differences existing in O2 sensors and effectors in the various arterial territories.

Pulmonary vascular reactivity to supplemental oxygen in Sherpa and lowlanders during gradual ascent to high altitude.

NEW FINDINGS: What is the central question of this study? How does hypoxic pulmonary vasoconstriction and the response to supplemental oxygen change over time at high altitude? What is the main finding and its importance? Lowlanders and partially de-acclimatized Sherpa both demonstrated pulmonary vascular responsiveness to supplemental oxygen that was maintained for 12 days' exposure to progressively increasing altitude. An additional 2 weeks' acclimatization at 5050 m altitude rendered the pulmonary vasculature minimally responsive to oxygen similar to the fully acclimatized non-ascent Sherpa. Additional hypoxic exposure at that time point did not augment hypoxic pulmonary vasoconstriction. ABSTRACT: Prolonged alveolar hypoxia leads to pulmonary vascular remodelling. We examined the time course at altitude, over which hypoxic pulmonary vasoconstriction goes from being acutely reversible to potentially irreversible. Study subjects were lowlanders (n = 20) and two Sherpa groups. All Sherpa were born and raised at altitude. One group (ascent Sherpa, n = 11) left altitude and after de-acclimatization in Kathmandu for ∼7 days re-ascended with the lowlanders over 8-10 days to 5050 m. The second Sherpa group (non-ascent Sherpa, n = 12) remained continuously at altitude. Pulmonary artery systolic pressure (PASP) and pulmonary vascular resistance (PVR) were measured while breathing ambient air and following supplemental oxygen. During ascent PASP and PVR increased in lowlanders and ascent Sherpa; however, with supplemental oxygen, lowlanders had significantly greater decrease in PASP (P = 0.02) and PVR (P = 0.02). After ∼14 days at 5050 m, PASP decreased with supplemental oxygen (mean decrease: 3.9 mmHg, 95% CI 2.1-5.7 mmHg, P < 0.001); however, PVR was unchanged (P = 0.49). In conclusion, PASP and PVR increased with gradual ascent to altitude and decreased via oxygen supplementation in both lowlanders and ascent Sherpa. Following ∼14 days at 5050 m altitude, there was no change in PVR to hypoxia or O2  supplementation in lowlanders or either Sherpa group. These data show that both duration of exposure and residential altitude influence the pulmonary vascular responses to hypoxia.

SARS-CoV-2 mitochondriopathy in COVID-19 pneumonia exacerbates hypoxemia.

RATIONALE: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes COVID-19 pneumonia. We hypothesize that SARS-CoV-2 causes alveolar injury and hypoxemia by damaging mitochondria in airway epithelial cells (AEC) and pulmonary artery smooth muscle cells (PASMC), triggering apoptosis and bioenergetic impairment, and impairing hypoxic pulmonary vasoconstriction (HPV), respectively. OBJECTIVES: We examined the effects of: A) human betacoronaviruses, SARS-CoV-2 and HCoV-OC43, and individual SARS-CoV-2 proteins on apoptosis, mitochondrial fission, and bioenergetics in AEC; and B) SARS-CoV-2 proteins and mouse hepatitis virus (MHV-1) infection on HPV. METHODS: We used transcriptomic data to identify temporal changes in mitochondrial-relevant gene ontology (GO) pathways post-SARS-CoV-2 infection. We also transduced AECs with SARS-CoV-2 proteins (M, Nsp7 or Nsp9) and determined effects on mitochondrial permeability transition pore (mPTP) activity, relative membrane potential, apoptosis, mitochondrial fission, and oxygen consumption rates (OCR). In human PASMC, we assessed the effects of SARS-CoV-2 proteins on hypoxic increases in cytosolic calcium, an HPV proxy. In MHV-1 pneumonia, we assessed HPV via cardiac catheterization and apoptosis using the TUNEL assay. RESULTS: SARS-CoV-2 regulated mitochondrial apoptosis, mitochondrial membrane permeabilization and electron transport chain (ETC) GO pathways within 2 hours of infection. SARS-CoV-2 downregulated ETC Complex I and ATP synthase genes, and upregulated apoptosis-inducing genes. SARS-CoV-2 and HCoV-OC43 upregulated and activated dynamin-related protein 1 (Drp1) and increased mitochondrial fission. SARS-CoV-2 and transduced SARS-CoV-2 proteins increased apoptosis inducing factor (AIF) expression and activated caspase 7, resulting in apoptosis. Coronaviruses also reduced OCR, decreased ETC Complex I activity and lowered ATP levels in AEC. M protein transduction also increased mPTP opening. In human PASMC, M and Nsp9 proteins inhibited HPV. In MHV-1 pneumonia, infected AEC displayed apoptosis and HPV was suppressed. BAY K8644, a calcium channel agonist, increased HPV and improved SpO2. CONCLUSIONS: Coronaviruses, including SARS-CoV-2, cause AEC apoptosis, mitochondrial fission, and bioenergetic impairment. SARS-CoV-2 also suppresses HPV by targeting mitochondria. This mitochondriopathy is replicated by transduction with SARS-CoV-2 proteins, indicating a mechanistic role for viral-host mitochondrial protein interactions. Mitochondriopathy is a conserved feature of coronaviral pneumonia that may exacerbate hypoxemia and constitutes a therapeutic target.

Chest dual-energy CT to assess the effects of steroids on lung function in severe COVID-19 patients.

BACKGROUND: Steroids have been shown to reduce inflammation, hypoxic pulmonary vasoconstriction (HPV) and lung edema. Based on evidence from clinical trials, steroids are widely used in severe COVID-19. However, the effects of steroids on pulmonary gas volume and blood volume in this group of patients are unexplored. OBJECTIVE: Profiting by dual-energy computed tomography (DECT), we investigated the relationship between the use of steroids in COVID-19 and distribution of blood volume as an index of impaired HPV. We also investigated whether the use of steroids influences lung weight, as index of lung edema, and how it affects gas distribution. METHODS: Severe COVID-19 patients included in a single-center prospective observational study at the intensive care unit at Uppsala University Hospital who had undergone DECT were enrolled in the current study. Patients' cohort was divided into two groups depending on the administration of steroids. From each patient's DECT, 20 gas volume maps and the corresponding 20 blood volume maps, evenly distributed along the cranial-caudal axis, were analyzed. As a proxy for HPV, pulmonary blood volume distribution was analyzed in both the whole lung and the hypoinflated areas. Total lung weight, index of lung edema, was estimated. RESULTS: Sixty patients were analyzed, whereof 43 received steroids. Patients not exposed to steroids showed a more extensive non-perfused area (19% vs 13%, p < 0.01) and less homogeneous pulmonary blood volume of hypoinflated areas (kurtosis: 1.91 vs 2.69, p < 0.01), suggesting a preserved HPV compared to patients treated with steroids. Moreover, patients exposed to steroids showed a significantly lower lung weight (953 gr vs 1140 gr, p = 0.01). A reduction in alveolar-arterial difference of oxygen followed the treatment with steroids (322 ± 106 mmHg at admission vs 267 ± 99 mmHg at DECT, p = 0.04). CONCLUSIONS: The use of steroids might cause impaired HPV and might reduce lung edema in severe COVID-19. This is consistent with previous findings in other diseases. Moreover, a reduced lung weight, as index of decreased lung edema, and a more homogeneous distribution of gas within the lung were shown in patients treated with steroids. TRIAL REGISTRATION: Clinical Trials ID: NCT04316884, Registered March 13, 2020.

Blunted hypoxic pulmonary vasoconstriction in apnoea divers.

NEW FINDINGS: What is the central question of this study? Does the hyperbaric, hypercapnic, acidotic, hypoxic stress of apnoea diving lead to greater pulmonary vasoreactivity and increased right heart work in apnoea divers? What is the main finding and its importance? Compared with sex- and age-matched control subjects, divers experienced significantly less change in total pulmonary resistance in response to short-duration isocapnic hypoxia. With oral sildenafil (50 mg), there were no differences in total pulmonary resistance between groups, suggesting that divers can maintain normal pulmonary artery tone in hypoxic conditions. Blunted hypoxic pulmonary vasoconstriction might be beneficial during apnoea diving. ABSTRACT: Competitive apnoea divers dive repetitively to depths >50 m. During the final portions of ascent, divers experience significant hypoxaemia. Additionally, hyperbaria during diving increases thoracic blood volume while simultaneously reducing lung volume and increasing pulmonary artery pressure. We hypothesized that divers would have exaggerated hypoxic pulmonary vasoconstriction, leading to increased right heart work owing to their repetitive hypoxaemia and hyperbaria, and that the administration of sildenafil would have a greater effect in reducing pulmonary resistance in divers. We recruited 16 divers (Divers) and 16 age- and sex-matched non-diving control subjects (Controls). Using a double-blinded, placebo-controlled, cross-over design, participants were evaluated for normal cardiac and lung function, then their cardiopulmonary responses to 20-30 min of isocapnic hypoxia (end-tidal partial pressure of O2  = 50 mmHg) were measured 1 h after ingestion of 50 mg sildenafil or placebo. Cardiac structure and cardiopulmonary function were similar at baseline. With placebo, Divers had a significantly smaller increase in total pulmonary resistance than Controls after 20-30 min isocapnic hypoxia (change -3.85 ± 72.85 vs. 73.74 ± 91.06 dyns cm-5 , P = 0.0222). With sildenafil, Divers and Controls had similar blunted increases in total pulmonary resistance after 20-30 min of hypoxia. Divers also had a significantly lower systemic vascular resistance after sildenafil in normoxia. These data indicate that repetitive apnoea diving leads to a blunted hypoxic pulmonary vasoconstriction. We suggest that this is a beneficial adaption allowing for increased cardiac output with reduced right heart work and thus reducing cardiac oxygen utilization in hypoxaemic conditions.