How Do Mechanics Guide Fibroblast Activity? Complex Disruptions during Emphysema Shape Cellular Responses and Limit Research

The emphysema death toll has steadily risen over recent decades, causing the disease to become the third most common cause of death worldwide in 2019. Emphysema is currently incurable and could be due to a genetic condition (Alpha-1 antitrypsin deficiency) or exposure to pollutants/irritants, such as cigarette smoke or poorly ventilated cooking fires. Despite the growing burden of emphysema, the mechanisms behind emphysematous pathogenesis and progression are not fully understood by the scientific literature. A key aspect of emphysematous progression is the destruction of the lung parenchyma extracellular matrix (ECM), causing a drastic shift in the mechanical properties of the lung (known as mechanobiology). The mechanical properties of the lung such as the stiffness of the parenchyma (measured as the elastic modulus) and the stretch forces required for inhalation and exhalation are both reduced in emphysema. Fibroblasts function to maintain the structural and mechanical integrity of the lung parenchyma, yet, in the context of emphysema, these fibroblasts appear incapable of repairing the ECM, allowing emphysema to progress. This relationship between the disturbances in the mechanical cues experienced by an emphysematous lung and fibroblast behaviour is constantly overlooked and consequently understudied, thus warranting further research. Interestingly, the failure of current research models to integrate the altered mechanical environment of an emphysematous lung may be limiting our understanding of emphysematous pathogenesis and progression, potentially disrupting the development of novel treatments. This review will focus on the significance of emphysematous lung mechanobiology to fibroblast activity and current research limitations by examining: (1) the impact of mechanical cues on fibroblast activity and the cell cycle, (2) the potential role of mechanical cues in the diminished activity of emphysematous fibroblasts and, finally, (3) the limitations of current emphysematous lung research models and treatments as a result of the overlooked emphysematous mechanical environment.

Phenotypic Clusters On Computed Tomography Reflects Asthma Heterogeneity And Severity

Background: Asthma comprises heterogeneous inflammatory airway disorders whose classification has not been established. Quantitative computed tomography (QCT) methods can differentiate lung disease using accurate assessment of location, extent, and severity of the disease. This study aimed to identify heterogeneous asthmatic groups by QCT metrics of airway and parenchymal structure, which is associated with radiologists’ visual analysis and bronchodilator responses in a prospective design.Methods: Using the input from QCT-based metrics, including hydraulic diameter (Dh), luminal wall thickness (WT), functional small airway disease (fSAD), and emphysematous lung (Emph), a cluster analysis was performed and compared with grouping based on site of airway involvement and remodeling evaluated by radiologists.Results: 61 asthmatics were grouped into four clusters with different clinical severities. From C1 to C4, more severe lung function deterioration, higher fixed obstruction rate, and more frequent asthma exacerbation in 5-year follow-up were observed. C1 presented non-severe asthma with increased WT, Dh of proximal airways, and fSAD. C2 was mixed with non-severe and severe asthma, which had reserved bronchodilator responses of proximal airways. C3 and C4 presented severe asthmatics that exhibited reduced Dh of proximal airway and its bronchodilator responsiveness; C3 was severe allergic asthma without fSAD, while C4 was ex-smokers with significantly high fSAD% and Emph%. These clusters were correlated with the grouping by radiologists and their clinical outcomes.Conclusions: Four QCT imaging-based clusters with distinct structural and functional changes in proximal and small airways can stratify heterogeneous asthmatics and may serve as complementary tools for predicting future asthma outcomes.

Hypoimmune induced pluripotent stem cell–derived cell therapeutics treat cardiovascular and pulmonary diseases in immunocompetent allogeneic mice

The emerging field of regenerative cell therapy is still limited by the few cell types that can reliably be differentiated from pluripotent stem cells and by the immune hurdle of commercially scalable allogeneic cell therapeutics. Here, we show that gene-edited, immune-evasive cell grafts can survive and successfully treat diseases in immunocompetent, fully allogeneic recipients. Transplanted endothelial cells improved perfusion and increased the likelihood of limb preservation in mice with critical limb ischemia. Endothelial cell grafts transduced to express a transgene for alpha1-antitrypsin (A1AT) successfully restored physiologic A1AT serum levels in mice with genetic A1AT deficiency. This cell therapy prevented both structural and functional changes of emphysematous lung disease. A mixture of endothelial cells and cardiomyocytes was injected into infarcted mouse hearts, and both cell types orthotopically engrafted in the ischemic areas. Cell therapy led to an improvement in invasive hemodynamic heart failure parameters. Our study supports the development of hypoimmune, universal regenerative cell therapeutics for cost-effective treatments of major diseases.

Spontaneous pneumothorax: some aspects of etiology, pathogenesis and treatment (literature review)

The review article discusses the prevalence, etiology, pathogenesis, and treatment of spontaneous pneumothorax. The vascular, mechanical, obstructive, infectious, and enzymatic theories of the occurrence of emphysematous lung changes as the main cause of developing spontaneous pneumothorax are described; the role of smoking as the main etiological factor and its influence on the recurrence rate of spontaneous pneumothorax are studied. The issues of choosing primary cure tactic are considered. The effectiveness of conservative treatment, puncture and drainage of the pleural cavity as methods of treatment and pleurodesis for the prevention of recurrences of spontaneous pneumothorax are described. A comparativeassessment of various methods of pleural cavity obliteration is given: chemical pleurodesis (by sterile talc, minocycline, povidone-iodine, 50% glucose solution, autologous blood and its components, autologous adipose tissue, pseudomonas aeruginosa sensitive hemagglutinin, picibanil), apical pleurectomy, pleuroabrasion. The experience of using YAG-ND and CO2 as methods of physical pleurodesis, intraoperative Staple Line Coverage with polyglyconic acid and fibrin gel is described. The necessity of active surgical tactic in the treatment of patients with spontaneous pneumothorax developed on the base of undifferentiated connective tissue dysplasia has been substantiated. The advantages, disadvantages, indications and contrindications to different ways of surgical treatment (thoracotomy, video-assisted minithoracotomy, thoracoscopy) are discussed. The strategy for choosing treatment methods depending on the volume of pneumothorax, the severity of bullous changes, the presence of concomitant diseases, chronic obstructive pulmonary disease, and the value of the Charlson comorbidity index is considered. The expediency of using video-assisted minithoracotomy as the safest and most effective method of surgical treatment of spontaneous pneumothorax has been substantiated. The effectiveness of surgical interventions depending on the timing of their implementation is considered.

Surgical management of congenital lobar emphysema associated with CHD

Congenital lobar emphysema is often associated with CHD in early infancy; however, the surgical strategy for this condition is still controversial. We report three successful cases of emphysematous lung lobectomy before the surgical repair of associated CHD. Aggressive lobectomy preceding cardiac interventions is advised when the management of congenital lobar emphysema is difficult.