Synergistic Detrimental Effects of Cigarette Smoke, Alcohol, and SARS-CoV-2 in COPD Bronchial Epithelial Cells.

Lung conditions such as COPD, as well as risk factors such as alcohol misuse and cigarette smoking, can exacerbate COVID-19 disease severity. Synergistically, these risk factors can have a significant impact on immunity against pathogens. Here, we studied the effect of a short exposure to alcohol and/or cigarette smoke extract (CSE) in vitro on acute SARS-CoV-2 infection of ciliated human bronchial epithelial cells (HBECs) collected from healthy and COPD donors. We observed an increase in viral titer in CSE- or alcohol-treated COPD HBECs compared to untreated COPD HBECs. Furthermore, we treated healthy HBECs accompanied by enhanced lactate dehydrogenase activity, indicating exacerbated injury. Finally, IL-8 secretion was elevated due to the synergistic damage mediated by alcohol, CSE, and SARS-CoV-2 in COPD HBECs. Together, our data suggest that, with pre-existing COPD, short exposure to alcohol or CSE is sufficient to exacerbate SARS-CoV-2 infection and associated injury, impairing lung defences.

Controlled DCD lung transplantation: Circumventing imagined and real barriers-time for an international taskforce?

Controlled donation after circulatory death (DCD) has the potential to substantially increase the number of lung transplants thus offsetting some of the imbalance between need and organ availability. We examine the potential benefits associated with increased DCD utilization as well as the perceived barriers to the expansion of DCD. Solutions are offered as a means to expand DCD utilization across centers and nations.

Induction and maintenance immunosuppression in lung transplantation.

Immunosuppression for lung transplant recipients is a critical part of post-transplant care, to prevent acute and chronic rejection. Treatment protocols consist of induction and maintenance immunotherapy. Induction agents provide an immediate state of immunosuppression following transplantation and over time, and their use has become more commonplace. Several agents are available for clinical use, including anti-thymocyte globulin, alemtuzumab, and basiliximab, the latter being most commonly employed. Each induction agent has unique side effects and caveats to their use, of which we must be aware. Maintenance immunosuppression is initiated following transplant but requires multiple doses prior to reaching therapeutic levels. A calcineurin inhibitor, an anti-metabolite, and a corticosteroid are traditionally used, most commonly tacrolimus, mycophenolate mofetil, and prednisone. Dosing regimens and goal trough levels vary and are tailored to a patient's clinical status and duration post-transplant. Future clinical studies may be able to assist in determining the optimal induction and maintenance immunosuppression regimens. In the interim, we use cohort and registry data to guide our therapies.

Successful lung transplantation with graft recovered after thoracoabdominal normothermic perfusion from donor after circulatory death.

Lung transplantation with lungs procured from donors after circulatory death (DCD) has been established as an alternative technique to traditional donation after brain death (DBD) with comparable outcomes. Recently, in situ thoracoabdominal normothermic regional perfusion (TA-NRP) has emerged as a novel technique employed in the procurement of cardiac allografts after circulatory death. TA-NRP, in contrast to ex situ machine perfusion, has the advantage of allowing in situ assessment of donor organs prior to final acceptance. However, there are some concerns that this technique may adversely impact the quality of lung allografts. Here, we present a case of a successful bilateral sequential lung transplantation in a patient with postinflammatory pulmonary fibrosis due to acute respiratory distress syndrome (ARDS), with lungs procured after normothermic in situ lung perfusion. Apart from the lungs, heart, liver, and kidneys were also successfully transplanted from this donor.

Pulmonary Hypertensive Changes Secondary to COVID-19 Pneumonia in a Chronically SARS-CoV-2-Infected Bilateral Lung Explant.

COVID-19, the syndrome caused by the novel coronavirus SARS-CoV-2, has spread throughout the world, causing the death of at least three million people. For the over 81 million who have recovered, however, the long-term effects are only beginning to manifest. We performed a bilateral lung transplant on a 31-year-old male patient for chronic hypoxic respiratory failure, severe pulmonary hypertension and radiographically identified pulmonary fibrosis five months after an acute COVID-19 infection. The explant demonstrated moderate pulmonary vascular remodeling with intimal thickening and medial hypertrophy throughout, consistent with pulmonary hypertension. The parenchyma demonstrated an organizing lung injury in the proliferative phase, with severe fibrosis, histiocytic proliferation, type II pneumocyte hyperplasia, and alveolar loss consistent with known COVID-19 pneumonia complications.This report highlights a novel histologic finding in severe, chronic COVID-19. Although the findings in acute COVID-19 pneumonia have been well-examined at autopsy, the chronic course of this complex disease is not yet understood. The case presented herein suggests that COVID-induced pulmonary hypertension may become more common as more patients survive severe SARS-CoV-2-related pneumonia. Pulmonologists and pulmonary pathologists should be aware of this possible association and look for the clinical, radiographic, and histologic criteria in the appropriate clinical setting.

ISHLT consensus document on lung transplantation in patients with connective tissue disease: Part I: Epidemiology, assessment of extrapulmonary conditions, candidate evaluation, selection criteria, and pathology statements.

Patients with connective tissue disease (CTD) and advanced lung disease are often considered suboptimal candidates for lung transplantation (LTx) due to their underlying medical complexity and potential surgical risk. There is substantial variability across LTx centers regarding the evaluation and listing of these patients. The International Society for Heart and Lung Transplantation-supported consensus document on lung transplantation in patients with CTD standardization aims to clarify definitions of each disease state included under the term CTD, to describe the extrapulmonary manifestations of each disease requiring consideration before transplantation, and to outline the absolute contraindications to transplantation allowing risk stratification during the evaluation and selection of candidates for LTx.

Combination plate and band fixation for primary closure in bilateral lung transplantation.

BACKGROUND: Sternal complications are common following transverse thoracosternotomy in patients undergoing bilateral lung transplantation. We present a single-institution experience using a next generation rigid fixation system for primary sternal closure following transverse sternotomy for bilateral lung transplantation. METHODS: Retrospective review was performed on all patients who had bilateral sequential lung transplants utilizing a transverse thoracosternotomy from 2016 to 2020. Demographics, baseline characteristics, peri-operative data, and outcomes were collected, reviewed and summarized. Two groups of patients were identified: wire cerclage (Group A), combination plate-and-band rigid fixation (Group B). The primary outcome was sternal complications, which were divided into mechanical and non-mechanical. RESULTS: Twenty-two patients met inclusion criteria. Three patients (13.6%) were in Group A, nineteen patients (86.4%) in Group B. Two patients in each Group A (66.6%) and Group B (10.5%) experienced a sternal complication. Sternal complications included sternal dehiscence (2), sternal malunion (1), and surgical site infection (1). One patient with plate-and-band fixation (5.2%) had a mechanical sternal complication. Three patients required reoperation secondary to sternal complication. CONCLUSIONS: The utilization of a combination plate-and-band rigid fixation system for primary closure is safe and may be an effective method to reduce sternal complications following transverse thoracosternotomy for lung transplantation.

Care of the Transgender Patient with a Pulmonary Complaint.

Individuals who identify with a gender not typically associated with their sex assigned at birth are a growing population worldwide. Guidelines to help healthcare providers navigate the care of gender minorities (GMs) are often aimed at primary care providers and may be too general for subspecialists. Pulmonologists may see GM individuals for a variety of reasons, and no reference exists that contains relevant information about GM-specific care, including unique conditions to consider. A systematic review was completed to identify unique characteristics in caring for GM patients with a pulmonary complaint.

TGF-ß1-induced miR-424 promotes pulmonary myofibroblast differentiation by targeting Slit2 protein expression.

Idiopathic pulmonary fibrosis (IPF) is a devastating interstitial lung disease with irreversible loss of lung tissue and function. Myofibroblasts in the lung are key cellular mediators of IPF progression. Transforming growth factor (TGF)-ß1, a major profibrogenic cytokine, induces pulmonary myofibroblast differentiation, and emerging evidence has established the importance of microRNAs (miRs) in the development of IPF. The objective of this study was to define the pro-fibrotic roles and mechanisms of miRs in TGF-ß1-induced pulmonary myofibroblast differentiation. Using RNA sequencing, we identified miR-424 as an important TGF-ß1-induced miR in human lung fibroblasts (HLFs). Quantitative RT-PCR confirmed that miR-424 expression was increased by 2.6-fold in HLFs in response to TGF-ß1 and was 1.7-fold higher in human fibrotic lung tissues as compared to non-fibrotic lung tissues. TGF-ß1-induced upregulation of miR-424 was blocked by the Smad3 inhibitor SIS3, suggesting the involvement of this canonical TGF-ß1 signaling pathway. Transfection of a miR-424 hairpin inhibitor into HLFs reduced TGF-ß1-induced expression of classic myofibroblast differentiation markers including ɑ-smooth muscle actin (ɑ-SMA) and connective tissue growth factor (CTGF), whereas a miR-424 mimic significantly enhanced TGF-ß1-induced myofibroblast differentiation. In addition, TGF-ß1 induced Smad3 phosphorylation in HLFs, and this response was reduced by the miR-424 inhibitor. In silico analysis identified Slit2, a protein that inhibits TGF-ß1 profibrogenic signaling, as a putative target of regulation by miR-424. Slit2 is less highly expressed in human fibrotic lung tissues than in non-fibrotic lung tissues, and knockdown of Slit2 by its siRNA enhanced TGF-ß1-induced HLF differentiation. Overexpression of a miR-424 mimic down-regulated expression of Slit2 but not the Slit2 major receptor ROBO1 in HLFs. Luciferase reporter assays showed that the miR-424 mimic represses Slit2 3' untranslated region (3'-UTR) reporter activity, and mutations at the seeding regions in the 3'-UTR of Slit2 abolish this inhibition. Together, these data demonstrate a pro-fibrotic role of miR-424 in TGF-ß1-induced HLF differentiation. It functions as a positive feed-back regulator of the TGF-ß1 signaling pathway by reducing expression of the negative regulator Slit2. Thus, targeting miR-424 may provide a new therapeutic strategy to prevent myofibroblast differentiation and IPF progression.