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Highlights • The Angiotensin system has been implicated in the pathogenesis of COVID-19. • Functional ACE/ACE2 polymorphisms might contribute to the outcome of COVID-19. • Severe COVID-19 was associated with hypertension, male gender, and ACE-DD genotype. • The ACE2 polymorphism was not associated with the disease outcome. • ACE2 showed no coding variants that could explain an increased risk of COVID-19., The Angiotensin system is implicated in the pathogenesis of COVID-19. First, ACE2 is the cellular receptor for SARS-CoV-2, and expression of the ACE2 gene could regulate the individuaĺs susceptibility to infection. In addition, the balance between ACE1 and ACE2 activity has been implicated in the pathogenesis of respiratory diseases and could play a role in the severity of COVID-19. Functional ACE1/ACE2 gene polymorphisms have been associated with the risk of cardiovascular and pulmonary diseases, and could thus also contribute to the outcome of COVID-19. We studied 204 COVID-19 patients (137 non-severe and 67 severe-ICU cases) and 536 age-matched controls. The ACE1 insertion/deletion and ACE2 rs2285666 polymorphism were determined. Variables frequencies were compared between the groups by logistic regression. We also sequenced the ACE2 coding nucleotides in a group of patients. Severe COVID-19 was associated with hypertension male gender (p

The chemokine receptor CCR5 has been implicated in COVID-19. CCR5 and its ligands are overexpressed in patients. The pharmacological targeting of CCR5 would improve the COVID-19 severity. We sought to investigate the role of the CCR5-Δ32 variant (rs333) in COVID-19. The CCR5-Δ32 was genotyped in 801 patients (353 in the intensive care unit, ICU) and 660 healthy controls, and the deletion was significantly less frequent in hospitalysed COVID-19 than in healthy controls (p = 0.01, OR = 0.66, 95%CI = 0.49-0.88). Of note, we did not find homozygotes among the patients, compared to 1% of the controls. The CCR5 transcript was measured in leukocytes from 85 patients and 40 controls. We found a significantly higher expression of the CCR5 transcript among the patients, with significant difference when comparing the non-deletion carriers (controls = 35; patients = 81; p = 0.01). ICU-patients showed non-significantly higher expression than no-ICU cases. Our study points to CCR5 as a genetic marker for COVID-19. The pharmacological targeting of CCR5 should be a promising treatment for COVID-19.

Matrix metalloproteinases can modulate the inflammatory response through processing of cyto- and chemokines. Among them, MMP-14 is a non-dispensable collagenase responsible for the activation of other enzymes, triggering a proteolytic cascade. To identify the role of MMP-14 during the pro-inflammatory response, wildtype and Mmp14 −/− mice were challenged with lipopolysaccharide. MMP-14 levels decreased after endotoxemia. Mutant animals showed 100% mortality, compared to 50% in wildtype mice. The increased mortality was related to a more severe lung injury, an impaired lung MMP-2 activation, and increased levels of the alarmin S100A9. There were no differences in the expression of other mediators including Il6, Cxcl2, Tgfb, Il10, or S100a8. A similar result was observed in lung explants of both genotypes cultured in presence of lipopolysaccharide. In this ex vivo model, exogenous activated MMP-2 ameliorated the observed increase in alarmins. Samples from septic patients showed a decrease in serum MMP-14 and activated MMP-2 compared to non-septic critically ill patients. These results demonstrate that the MMP-14-MMP-2 axis is downregulated during sepsis, leading to a proinflammatory response involving S100A9 and a more severe lung injury. This anti-inflammatory role of MMP-14 could have a therapeutic value in sepsis. • MMP-14 levels decrease in lungs from endotoxemic mice and serum from septic patients. • Mmp14 −/− mice show increased lung injury and mortality following endotoxemia. • Absence of Mmp14 decreases activated MMP-2 and increases S100A9 levels in lung tissue. • MMP-14 ameliorates inflammation by promoting S100A9 cleavage by activated MMP-2.

OBJECTIVES: Mechanical ventilation can cause ventilator-induced brain injury via afferent vagal signaling and hippocampal neurotransmitter imbalances. The triggering mechanisms for vagal signaling during mechanical ventilation are unknown. The objective of this study was to assess whether pulmonary transient receptor potential vanilloid type-4 (TRPV4) mechanoreceptors and vagal afferent purinergic receptors (P2X) act as triggers of ventilator-induced brain injury. DESIGN: Controlled, human in vitro and ex vivo studies, as well as murine in vivo laboratory studies. SETTING: Research laboratory. SUBJECTS: Wild-type, TRPV4-deficient C57BL/6J mice, 8-10 weeks old. Human postmortem lung tissue and human lung epithelial cell line BEAS-2B. INTERVENTION: Mice subjected to mechanical ventilation were studied using functional MRI to assess hippocampal activity. The effects of lidocaine (a nonselective ion-channel inhibitor), P2X-purinoceptor antagonist (iso-PPADS), or genetic TRPV4 deficiency on hippocampal dopamine-dependent pro-apoptotic signaling were studied in mechanically ventilated mice. Human lung epithelial cells (BEAS-2B) were used to study the effects of mechanical stretch on TRPV4 and P2X expression and activation. TRPV4 levels were measured in postmortem lung tissue from ventilated and nonventilated patients. MEASUREMENTS AND MAIN RESULTS: Hippocampus functional MRI analysis revealed considerable changes in response to the increase in tidal volume during mechanical ventilation. Intratracheal lidocaine, iso-PPADS, and TRPV4 genetic deficiency protected mice against ventilationinduced hippocampal pro-apoptotic signaling. Mechanical stretch in both, BEAS-2B cells and ventilated wild-type mice, resulted in TRPV4 activation and reduced Trpv4 and P2x expression. Intratracheal replenishment of adenosine triphosphate in Trpv4 mice abrogated the protective effect of TRPV4 deficiency. Autopsy lung tissue from ventilated patients showed decreased lung TRPV4 levels compared with nonventilated patients. CONCLUSIONS: TRPV4 mechanosensors and purinergic receptors are involved in the mechanisms of ventilator-induced brain injury. Inhibition of this neural signaling, either using nonspecific or specific inhibitors targeting the TRPV4/adenosine triphosphate/P2X signaling axis, may represent a novel strategy to prevent or treat ventilator-induced brain injury.

Objective:Acute respiratory failure in hematological patients is related to a high mortality. Noninvasive mechanical ventilation may benefit a subset of these patients, but the overall effect on mortality and the risks derived from its failure are unclear. Our objective was to review the impact of i

Background Lung strain, defined as the ratio between end-inspiratory volume and functional residual capacity, is a marker of the mechanical load during ventilation. However, changes in lung volumes in response to pressures may occur in injured lungs and modify strain values. The objective of this study was to clarify the role of recruitment in strain measurements. Methods Six oleic acid–injured pigs were ventilated at positive end-expiratory pressure (PEEP) 0 and 10 cm H2O before and after a recruitment maneuver (PEEP = 20 cm H2O). Lung volumes were measured by helium dilution and inductance plethysmography. In addition, six patients with moderate-to-severe acute respiratory distress syndrome were ventilated with three strategies (peak inspiratory pressure/PEEP: 20/8, 32/8, and 32/20 cm H2O). Lung volumes were measured in computed tomography slices acquired at end-expiration and end-inspiration. From both series, recruited volume and lung strain (total, dynamic, and static) were computed. Results In the animal model, recruitment caused a significant decrease in dynamic strain (from [mean ± SD] 0.4 ± 0.12 to 0.25 ± 0.07, P < 0.01), while increasing the static component. In patients, total strain remained constant for the three ventilatory settings (0.35 ± 0.1, 0.37 ± 0.11, and 0.32 ± 0.1, respectively). Increases in tidal volume had no significant effects. Increasing PEEP constantly decreased dynamic strain (0.35 ± 0.1, 0.32 ± 0.1, and 0.04+0.03, P < 0.05) and increased static strain (0, 0.06 ± 0.06, and 0.28 ± 0.11, P < 0.05). The changes in dynamic and total strain among patients were correlated to the amount of recruited volume. An analysis restricted to the changes in normally aerated lung yielded similar results. Conclusion Recruitment causes a shift from dynamic to static strain in early acute respiratory distress syndrome.

Neutrophils are key players in acute lung injury. Once recruited from the circulation, these cells release cytotoxic molecules that lead to tissue disruption, so their blockade has been advocated to prevent lung damage. However, lung injury also occurs during neutropenia and usually involves a very poor outcome. There is emerging evidence that neutrophils not only contribute to that early damage but also orchestrate later repair. Neutrophils promote epithelial proliferation and are a source of proteases, which are required for the processing of the collagen scar and facilitation of cell migration. This article reviews the effects of neutrophils in repair after acute lung injury, focusing on their role as biovectors for proteases and other molecules involved in tissue remodeling.

BackgroundNeutrophils may cause tissue disruption during migration and by releasing cytotoxic molecules. However, the benefits of neutrophil depletion observed in experimental models of lung injury do not correspond with the poor outcome of neutropenic patients.MethodsTo clarify the role of neutrophils during repair, mice with ventilator induced lung injury (VILI) were rendered neutropenic after damage, and followed for 48 hours of spontaneous breathing. Lungs were harvested and inflammatory mediators and matrix metalloproteinases measured. Bronchoalveolar lavage fluid (BALF) from ventilated patients with acute respiratory distress syndrome, with or without neutropenia, was collected, the same mediators measured and their effects in an ex vivo model of alveolar repair studied. Finally, neutropenic mice were treated after VILI with exogenous matrix metalloproteinase-9 (MMP-9).ResultsLungs from neutropenic animals showed delayed repair and displayed higher levels of tumour necrosis factor α, interferon γ and macrophage inflammatory protein 2, and absence of MMP-9. BALF from ventilated neutropenic patients with acute respiratory distress syndrome showed similar results. BALFs from neutropenic patients yielded a delayed closure rate of epithelial wounds ex vivo, which was improved by removal of collagen or addition of exogenous MMP-9. Lastly, treatment of neutropenic mice with exogenous MMP-9 after VILI reduced tissue damage without modifying cytokine concentrations.ConclusionRelease of MMP-9 from neutrophils is required for adequate matrix processing and lung repair.

The nuclear membrane acts as a mechanosensor that drives cellular responses following changes in the extracellular environment. Mechanically ventilated lungs are exposed to an abnormally high mechanical load that may result in clinically relevant alveolar damage. We report that mechanical ventilation in mice increased the expression of Lamin-A, a major determinant of nuclear membrane stiffness, in alveolar epithelial cells. Lamin-A expression increased and nuclear membrane compliance decreased in human bronchial epithelial cells after a mechanical stretch stimulus and in a murine model of lung injury after positive-pressure ventilation. Reducing Lamin-A maturation by depletion of the protease-encoding gene Zmpste24 preserved alveolar nuclear membrane compliance after mechanical ventilation in mice. Ventilator-induced proapoptotic gene expression changes and lung injury were reduced in mice lacking Zmpste24 compared to wild-type control animals. Similarly, treatment with the human immunodeficiency virus protease inhibitors lopinavir and ritonavir reduced the accumulation of Lamin-A at nuclear membranes and preserved nuclear membrane compliance after mechanical ventilation, mimicking the protective phenotype of Zmpste24-/- animals. These results show that the pathophysiological response to lung mechanical stretch is sensed by the nuclear membranes of lung alveolar cells, and suggest that protease inhibitors might be effective in preventing ventilator-induced lung injury.