GPER Activation Attenuates Lipopolysaccharide-Induced Acute Respiratory Distress Syndrome Sex-Dependently and Inhibits Alveolar Macrophage Activation

Background: Acute respiratory distress syndrome (ARDS), a common and critical disease, is clinically characterized by uncontrolled inflammation and alveolar-capillary barrier disruption. Estrogen can reportedly alleviate ARDS caused by numerous insults in mice. Moreover, the estradiol receptors α, not β,participated in E2-induced attenuation of ARDS. But the role of another estradiol receptor, G protein-coupled estradiol receptor 1 (GPER1) in ARDS are not undertood. This study is aimed to investigate the effect of GPER activation on LPS-induced ARDS in mice.Methods: Female mice were randomly subjected to bilateral ovarectomy (OVX) or sham surgery two weeks before lung injury. The GPER-selective agonist G1 or vehicle were intraperitoneally injected 0.5 h before intratracheal administration of LPS or phosphate-buffered saline in male and female mice. After 24 h, mice were sacrificed to collect blood, bronchoalveolar lavage fluid (BALF), and lung tissue. Histological injury and inflammatory cell infiltration in lung tissue, as well as cytokine and protein concentrations in BALF were determined. In vitro experiments were also performed on alveolar macrophages (MH-S cells) to investigate the effect of GPER activation on LPS-induced inflammatory responses.Results: Activation of GPER by G1 administration significantly ameliorated lung pathological damage, attenuated alveolar capillary barrier destruction, inhibited recruitment of inflammatory cells into alveoli, and decreased concentrations of the pro-inflammatory factors tumor necrosis factor α (TNF-α) and interleukin 6 (IL-6) in BALF of LPS-administered male and OVX female mice, but not intact female mice. In vitro experiments demonstrated that G1 pretreatment significantly inhibited LPS-mediated increases of TNF-α, IL-6, and MIP2 in a dose-dependent manner.Conclusions: These results demonstrated that GPER activation attenuated lung injury of male and OVX female mice by inhibiting the inflammatory response of alveolar macrophages.

Mesenchymal stromal cell-derived extracellular vesicles reduce lung inflammation and damage in nonclinical acute lung injury: Implications for COVID-19

Mesenchymal stem cell derived extracellular vesicles (MSC-EVs) are bioactive particles that evoke beneficial responses in recipient cells. We identified a role for MSC-EV in immune modulation and cellular salvage in a model of SARS-CoV-2 induced acute lung injury (ALI) using pulmonary epithelial cells and exposure to cytokines or the SARS-CoV-2 receptor binding domain (RBD). Whereas RBD or cytokine exposure caused a pro-inflammatory cellular environment and injurious signaling, impairing alveolar-capillary barrier function, and inducing cell death, MSC-EVs reduced inflammation and reestablished target cell health. Importantly, MSC-EV treatment increased active ACE2 surface protein compared to RBD injury, identifying a previously unknown role for MSC-EV treatment in COVID-19 signaling and pathogenesis. The beneficial effect of MSC-EV treatment was confirmed in an LPS-induced rat model of ALI wherein MSC-EVs reduced pro-inflammatory cytokine secretion and respiratory dysfunction associated with disease. MSC-EV administration was dose-responsive, demonstrating a large effective dose range for clinical translation. These data provide direct evidence of an MSC-EV-mediated improvement in ALI and contribute new insights into the therapeutic potential of MSC-EVs in COVID-19 or similar pathologies of respiratory distress.

Ideal alveolar gas defined by modal gas exchange in ventilation-perfusion distributions

Under the three-compartment model of ventilation-perfusion (VA/Q) scatter, Bohr-Enghoff calculation of alveolar deadspace fraction (VDA/VA) uses arterial CO2 partial pressure measurement as an approximation of "ideal" alveolar CO2(ideal PACO2). However, this simplistic model suffers from several inconsistencies. Modelling of realistic physiological distributions of VA and Q instead suggests an alternative concept of "ideal" alveolar gas at the VA/Q ratio where uptake or elimination rate of a gas is maximal. The alveolar-capillary partial pressure at this "modal" point equals the mean of expired alveolar and arterial partial pressures, regardless of VA/Q scatter severity or overall VA/Q. For example, modal ideal PACO2 can be estimated from Estimated modal ideal PACO2 = (PACO2+PaCO2)/2 Using a multicompartment computer model of log normal distributions of VA and Q, agreement of this estimate with the modal ideal PACO2 located at the VA/Q ratio of maximal compartmental VCO2 was assessed across a wide range of severity of VA/Q scatter and overall VA/Q ratio. Agreement of VDA/VA for CO2 from the Bohr equation using modal idealPCO2 with that using the estimated value was also assessed. Estimated modal ideal PACO2 agreed closely with modal ideal PACO2, intraclass correlation (ICC) > 99.9%. There was no significant difference between VDA/VACO2 using either value for ideal PACO2. Modal ideal PACO2 reflects a physiologically realistic concept of ideal alveolar gas where there is maximal gas exchange effectiveness in a physiological distribution of VA/Q, which is generalizable to any inert gas, and is practical to estimate from arterial and end-expired CO2 partial pressures.

Gene transfer of MRCKα rescues lipopolysaccharide-induced acute lung injury by restoring alveolar capillary barrier function

Acute Lung Injury/Acute Respiratory Distress Syndrome (ALI/ARDS) is characterized by alveolar edema accumulation with reduced alveolar fluid clearance (AFC), alveolar-capillary barrier disruption, and substantial inflammation, all leading to acute respiratory failure. Enhancing AFC has long been considered one of the primary therapeutic goals in gene therapy treatments for ARDS. We previously showed that electroporation-mediated gene delivery of the Na+, K+-ATPase β1 subunit not only increased AFC, but also restored alveolar barrier function through upregulation of tight junction proteins, leading to treatment of LPS-induced ALI in mice. We identified MRCKα as an interaction partner of β1 which mediates this upregulation in cultured alveolar epithelial cells. In this study, we investigate whether electroporation-mediated gene transfer of MRCKα to the lungs can attenuate LPS-induced acute lung injury in vivo. Compared to mice that received a non-expressing plasmid, those receiving the MRCKα plasmid showed attenuated LPS-increased pulmonary edema and lung leakage, restored tight junction protein expression, and improved overall outcomes. Interestingly, gene transfer of MRCKα did not alter AFC rates. Studies using both cultured microvascular endothelial cells and mice suggest that β1 and MRCKα upregulate junctional complexes in both alveolar epithelial and capillary endothelial cells, and that one or both barriers may be positively affected by our approach. Our data support a model of treatment for ALI/ARDS in which improvement of alveolar-capillary barrier function alone may be of more benefit than improvement of alveolar fluid clearance.

Anticoagulation is the Answer in Treating Non-Critical COVID-19 Patients

All autopsy studies demonstrated widespread thrombosis and alveolar-capillary microthrombi as the cause of death among patients with COVID-19. The autopsy studies are the gold standard for diagnostic accuracy and therapeutic strategies for any clinical scenario. The author initially observed that patients already taking therapeutic dose oral direct factor Xa inhibitors for an unrelated reason, have significantly better survival rates than those not taking any anticoagulants. This influenced the author to conduct a retrospective chart review of the Jackson Hospital (Alabama) hospitalized patients to evaluate the effect of variable doses of anticoagulation among COVID-19 patients. The study found that serum inflammatory bio-marker D-Dimer trends are associated with changes in oxygen requirement among patients with COVID-19 if patients present at an early stage and titration of Enoxaparin (anticoagulation) dose based on D-Dimer trends leads to increased patient survival.

Perioperative Pulmonary Atelectasis: Part I. Biology and Mechanisms

Pulmonary atelectasis is common in the perioperative period. Physiologically, it is produced when collapsing forces derived from positive pleural pressure and surface tension overcome expanding forces from alveolar pressure and parenchymal tethering. Atelectasis impairs blood oxygenation and reduces lung compliance. It is increasingly recognized that it can also induce local tissue biologic responses, such as inflammation, local immune dysfunction, and damage of the alveolar–capillary barrier, with potential loss of lung fluid clearance, increased lung protein permeability, and susceptibility to infection, factors that can initiate or exaggerate lung injury. Mechanical ventilation of a heterogeneously aerated lung (e.g., in the presence of atelectatic lung tissue) involves biomechanical processes that may precipitate further lung damage: concentration of mechanical forces, propagation of gas–liquid interfaces, and remote overdistension. Knowledge of such pathophysiologic mechanisms of atelectasis and their consequences in the healthy and diseased lung should guide optimal clinical management.