New Frontiers in Functional and Molecular Imaging of the Acutely Injured Lung: Pathophysiological Insights and Research Applications

This review focuses on the advances in the understanding of the pathophysiology of ventilator-induced and acute lung injury that have been afforded by technological development of imaging methods over the last decades. Examples of such advances include the establishment of regional lung mechanical strain as a determinant of ventilator-induced lung injury, the relationship between alveolar recruitment and overdistension, the regional vs. diffuse nature of pulmonary involvement in acute respiratory distress syndrome (ARDS), the identification of the physiological determinants of the response to recruitment interventions, and the pathophysiological significance of metabolic alterations in the acutely injured lung. Taken together, these advances portray multimodality imaging as the next frontier to both advance knowledge of the pathophysiology of these conditions and to tailor treatment to the individual patient’s condition.

Evaluation of Nano-Particulate-Matter-Induced Lung Injury in Mice Using Quantitative Micro-Computed Tomography

Nano-particulate matters (NPM) induced the lung injury in mice were evaluated using quantitative micro-computed tomography in the present article. It is an important negative effect of health problems that NPM exposure provokes changes in the lung injury. The micro-computed tomography (CT) to assess lung injury in mouse models has been investigated. The dynamic structural changes in a NPM-induced lung injury mouse mode were monitored. Adults female BALB/C mice were repeatedly exposed to NPM, and micro-CT scans were performed at day 0, 3, 5 and 9. Lung samples were also collected for histological analysis at each time point. The total lung volume, the injured lung volume, and the normal lung volume were defined and calculated volume during the phase of NPM-exposure on the mice. The total and injured lung volumes of NPM-exposed mice were significantly larger than those of the mice at day 5 and 9. The data from micro-CT was consistent with alveolar enlargement and destruction by histological quantification from pathological section. The study for NPM-induced lung injury model by micro-CT may extend our understanding of the distinct pathophysiology of NPM induced lung injury in mice.

Progesterone Aggravates Lung Fibrosis in a Mouse Model of Systemic Sclerosis

BackgroundGender-related factors have explained the higher prevalence of autoimmune diseases in women. Sex hormones play a key role in the immune system and parenchymal cells function; therefore, these hormones can be important in the pathogenesis of autoimmune diseases as a risk or beneficial factor. Lung fibrosis is the main cause of mortality in systemic sclerosis, a female predominant autoimmune disease. The objective of this study was to examine the effect of progesterone on lung fibrosis in a mouse model of systemic sclerosis.MethodsMice with bleomycin-induced lung fibrosis treated with progesterone subcutaneously for 21 and 28 days. Blood was collected for hormone and cytokine measurement at the end of treatment then, skin and lung tissues were harvested for histological assessment, gene expression, cytokine, hydroxyproline, and gelatinase measurement.ResultsTrichrome staining and hydroxyproline measurements showed that progesterone treatment increased the content of collagen in fibrotic and normal lung tissues. Progesterone increased α-SMA (P < 0.01), TGF- β (P < 0.05) and decreased MMP9 (P < 0.05) in fibrotic lung tissues. Also progesterone treatment decreased the gene expression of Col1a2 (P <0.05), Ctgf (P <01), End1 (0.001) in bleomycin- injured lung tissues. The serum level of TNF-α was decreased, but the serum level of cortisol was increased by progesterone treatment in fibrotic mice (P< 0.05).ConclusionOur results showed that progesterone aggravates lung fibrosis in a mouse model of systemic sclerosis.

Bioengineering Progress in Lung Assist Devices

Artificial lung technology is advancing at a startling rate raising hopes that it would better serve the needs of those requiring respiratory support. Whether to assist the healing of an injured lung, support patients to lung transplantation, or to entirely replace native lung function, safe and effective artificial lungs are sought. After 200 years of bioengineering progress, artificial lungs are closer than ever before to meet this demand which has risen exponentially due to the COVID-19 crisis. In this review, the critical advances in the historical development of artificial lungs are detailed. The current state of affairs regarding extracorporeal membrane oxygenation, intravascular lung assists, pump-less extracorporeal lung assists, total artificial lungs, and microfluidic oxygenators are outlined.

The Oxygen Dissociation Curve of Blood in COVID-19

COVID-19 hinders oxygen transport to the consuming tissues by at least 2 mechanisms: In the injured lung saturation of hemoglobin is compromised, in the tissues an associated anemia reduces the volume of delivered oxygen. For the first problem increased hemoglobin oxygen affinity (left shift of the oxygen dissociation curve ODC) is of advantage, for the 2nd, however, the contrary is the case. Indeed a right shift of the ODC has been found in former studies for anemia caused by reduced cell production or hemolysis. This resulted from increased 2,3-biphosphglycerate (2,3-BPG) concentration. In 3 investigations in COVID-19, however, no change of hemoglobin affinity was detected in spite of probably high [2,3-BPG]. The most plausible cause for this finding is formation of methemoglobin, which increases the oxygen affinity and thus apparently compensates for the 2,3-BPG effect. But this "useful effect" is cancelled by the concomitant reduction of functional hemoglobin. In the largest study on COVID-19 even a clear left shift of the ODC was detected when calculated from measurements in fresh blood rather than after equilibration with gases outside the body. This additional „in vivo" left shift possibly results from various factors (e. g. concentration changes of Cl-, 2,3-BPG, ATP, lactate, nitrocompounds, glutathione, glutamate, because of time delay between blood sampling and end of equilibration, or enlarged distribution space including interstitial fluid and is useful for O2 uptake in the lungs. Under discussion for therapy are the affinity-increasing 5-hydroxymethyl-2-furfural (5-HMF), erythropoiesis stimulating substances like erythropoietin, and methylene blue against MetHb formation.

Programming to S1PR1 + Endothelial Cells Promote Restoration of Vascular Integrity

Rationale: Increased endothelial permeability and defective repair are the hallmarks of several vascular diseases including acute lung injury (ALI). However, little is known about the intrinsic pathways activating the endothelial cell (EC) regenerative programs. Objective: Studies have invoked a crucial role of sphingosine-1-phosphate (S1P) in resolving endothelial hyperpermeability through the activation of the G-protein coupled receptor, sphingosine-1-phosphate receptor 1 (S1PR1). Here we addressed mechanisms of generation of a population of S1PR1 + EC and their pivotal role in restoring endothelial integrity. Methods and Results: Studies were made using inducible EC-S1PR1 -/- (iEC-S1PR1 -/- ) mice and S1PR1-GFP reporter mice to trace the generation of S1PR1 + EC. We observed in a mouse model of endotoxemia that S1P generation induced the programming of S1PR1 lo to S1PR1 + EC, which eventually comprised 80% of the lung EC. The cell transition was required for reestablishing the endothelial junctional barrier. We observed that conditional deletion of S1PR1 in EC increased endothelial permeability. RNA-seq analysis of S1PR1 + EC showed enrichment of genes regulating S1P synthesis and transport, specifically sphingosine kinase 1 (SPHK1) and SPNS2. Activation of transcription factors EGR1 and STAT3 was required for transcribing SPHK1 and SPNS2, respectively and both served to increase S1P production and amplify S1PR1 + EC transition. Furthermore, transplantation of S1PR1 + EC population into injured lung vasculature restored endothelial integrity. Conclusions: Our findings show that generation of the S1PR1 + EC population activates the endothelial regenerative program to mediate endothelial repair. Results raise the possibility of harnessing this pathway to restore vascular homeostasis in inflammatory vascular injury states.

Inhibition of the Lipoxin A4 and Resolvin D1 Receptor Impairs Host Response to Acute Lung Injury Caused by Pneumococcal Pneumonia in Mice

Resolution of the acute respiratory distress syndrome (ARDS) from pneumonia requires repair of the injured lung endothelium and alveolar epithelium, removal of neutrophils from the distal airspaces of the lung, and clearance of the pathogen. Previous studies have demonstrated the importance of specialized pro-resolving mediators (SPMs) in the regulation of host responses during inflammation. Although ARDS is commonly caused by Streptococcus pneumoniae, the role of Lipoxin A4 (LXA4) and Resolvin D1 (RvD1) in pneumococcal pneumonia is not well understood. In the present experimental study, we tested the hypothesis that endogenous SPMs play a role in the resolution of lung injury in a clinically relevant model of bacterial pneumonia. Blockade of ALX/FPR2, the receptor for LXA4 and RvD1, with the peptide WRW4 resulted in more pulmonary edema, greater protein accumulation in the air spaces, and increased bacteria accumulation in the air spaces and the blood. Inhibition of this receptor was also associated with decreased levels of pro-inflammatory cytokines. Even in the presence of antibiotic treatment, WRW4 inhibited the resolution of lung injury. In summary, these experiments demonstrated two novel findings: LXA4 and RvD1 contribute to the resolution of lung injury due to pneumococcal pneumonia, and the mechanism of their benefit likely includes augmenting bacterial clearance and reducing pulmonary edema via the restoration of lung alveolar-capillary barrier permeability.

A Review of Placenta and Umbilical Cord-Derived Stem Cells and the Immunomodulatory Basis of Their Therapeutic Potential in Bronchopulmonary Dysplasia

Bronchopulmonary dysplasia (BPD) is a devastating lung disorder of preterm infants as a result of an aberrant reparative response following exposures to various antenatal and postnatal insults. Despite sophisticated medical treatment in this modern era, the incidence of BPD remains unabated. The current strategies to prevent and treat BPD have met with limited success. The emergence of stem cell therapy may be a potential breakthrough in mitigating this complex chronic lung disorder. Over the last two decades, the human placenta and umbilical cord have gained increasing attention as a highly potential source of stem cells. Placenta-derived stem cells (PDSCs) and umbilical cord-derived stem cells (UCDSCs) display several advantages such as immune tolerance and are generally devoid of ethical constraints, in addition to their stemness qualities. They possess the characteristics of both embryonic and mesenchymal stromal/stem cells. Recently, there are many preclinical studies investigating the use of these cells as therapeutic agents in neonatal disease models for clinical applications. In this review, we describe the preclinical and clinical studies using PDSCs and UCDSCs as treatment in animal models of BPD. The source of these stem cells, routes of administration, and effects on immunomodulation, inflammation and regeneration in the injured lung are also discussed. Lastly, a brief description summarized the completed and ongoing clinical trials using PDSCs and UCDSCs as therapeutic agents in preventing or treating BPD. Due to the complexity of BPD, the development of a safe and efficient therapeutic agent remains a major challenge to both clinicians and researchers.

Spontaneous Breathing and Evolving Phenotypes of Lung Damage in Patients with COVID-19: Review of Current Evidence and Forecast of a New Scenario

The mechanisms of acute respiratory failure other than inflammation and complicating the SARS-CoV-2 infection are still far from being fully understood, thus challenging the management of COVID-19 patients in the critical care setting. In this unforeseen scenario, the role of an individual’s excessive spontaneous breathing may acquire critical importance, being one potential and important driver of lung injury and disease progression. The consequences of this acute lung damage may impair lung structure, forecasting the model of a fragile respiratory system. This perspective article aims to analyze the progression of injured lung phenotypes across the SARS-CoV-2 induced respiratory failure, pointing out the role of spontaneous breathing and also tackling the specific respiratory/ventilatory strategy required by the fragile lung type.