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Frontiers in Immunology 2023Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of...
INTRODUCTION
Acute respiratory distress syndrome (ARDS) is a common complication of influenza virus (IV) infection. During ARDS, alveolar protein concentrations often reach 40-90% of plasma levels, causing severe impairment of gas exchange and promoting deleterious alveolar remodeling. Protein clearance from the alveolar space is at least in part facilitated by the multi-ligand receptor megalin through clathrin-mediated endocytosis.
METHODS
To investigate whether IV infection impairs alveolar protein clearance, we examined albumin uptake and megalin expression in MLE-12 cells and alveolar epithelial cells (AEC) from murine precision-cut lung slices (PCLS) and in vivo, under IV infection conditions by flow cytometry and western blot. Transcriptional levels from AEC and broncho-alveolar lavage (BAL) cells were analyzed in an in-vivo mouse model by RNAseq.
RESULTS
IV significantly downregulated albumin uptake, independently of activation of the TGF-β1/GSK3β axis that has been previously implicated in the regulation of megalin function. Decreased plasma membrane abundance, total protein levels, and mRNA expression of megalin were associated with this phenotype. In IV-infected mice, we identified a significant upregulation of matrix metalloproteinase (MMP)-14 in BAL fluid cells. Furthermore, the inhibition of this protease partially recovered total megalin levels and albumin uptake.
DISCUSSION
Our results suggest that the previously described MMP-driven shedding mechanisms are potentially involved in downregulation of megalin cell surface abundance and clearance of excess alveolar protein. As lower alveolar edema protein concentrations are associated with better outcomes in respiratory failure, our findings highlight the therapeutic potential of a timely MMP inhibition in the treatment of IV-induced ARDS.
Topics: Animals; Mice; Alveolar Epithelial Cells; Low Density Lipoprotein Receptor-Related Protein-2; Biological Transport; Albumins; Orthomyxoviridae Infections; Orthomyxoviridae
PubMed: 37727782
DOI: 10.3389/fimmu.2023.1260973 -
European Journal of Immunology Oct 2023Alveolar macrophages (alvMs) play an important role for maintenance of lung function by constant removal of cellular debris in the alveolar space. They further...
Alveolar macrophages (alvMs) play an important role for maintenance of lung function by constant removal of cellular debris in the alveolar space. They further contribute to defense against microbial or viral infections and limit tissue damage during acute lung injury. alvMs arise from embryonic progenitor cells, seed the alveoli before birth, and have life-long self-renewing capacity. However, recruited monocytes may also help to restore the alvM population after depletion caused by toxins or influenza virus infection. At present, the population dynamics and cellular plasticity of alvMs during allergic lung inflammation is poorly defined. To address this point, we used a mouse model of Aspergillus fumigatus-induced allergic lung inflammation and observed that Th2-derived IL-4 and IL-13 caused almost complete disappearance of alvMs. This effect required STAT6 expression in alvMs and also occurred in various other settings of type 2 immunity-mediated lung inflammation or administration of IL-4 complexes to the lung. In addition, Th2 cells promoted conversion of alvMs to alternatively activated macrophages and multinucleated giant cells. Given the well-established role of alvMs for maintenance of lung function, this process may have implications for resolution of inflammation and tissue homeostasis in allergic asthma.
Topics: Mice; Animals; Macrophages, Alveolar; Interleukin-4; Lung; Asthma; Inflammation; Pneumonia; Pulmonary Eosinophilia
PubMed: 37452620
DOI: 10.1002/eji.202350475 -
Academic Radiology Dec 2023This systematic review and meta-analysis aimed to investigate the radiological predictors of post-coronavirus disease 19 (COVID-19) pulmonary fibrosis and incomplete... (Meta-Analysis)
Meta-Analysis Review
RATIONALE AND OBJECTIVES
This systematic review and meta-analysis aimed to investigate the radiological predictors of post-coronavirus disease 19 (COVID-19) pulmonary fibrosis and incomplete absorption of pulmonary lesions.
MATERIALS AND METHODS
We systematically searched PubMed, EMBASE, and Web of Science for studies reporting the predictive value of radiological findings in patients with post-COVID-19 lung residuals published through November 11, 2022. The pooled odds ratios with a 95% confidence interval (CI) were assessed. The random-effects model was used due to the heterogeneity of the true effect sizes.
RESULTS
We included 11 studies. There were 1777 COVID-19-positive patients, and 1014 (57%) were male. All studies used chest computed tomography (CT) as a radiologic tool. Moreover, chest X-ray (CXR) and lung ultrasound were used in two studies, along with a CT scan. CT severity score (CTSS), Radiographic Assessment of Lung Edema score (RALE), interstitial score, lung ultrasound score (LUS), patchy opacities, abnormal CXR, pleural traction, and subpleural abnormalities were found to be predictors of post-COVID-19 sequels. CTSS and consolidations were the most common predictors among included studies. Pooled analysis revealed that pulmonary residuals in patients with initial consolidation are about four times more likely than in patients without this finding (odds ratio: 3.830; 95% CI: 1.811-8.102, I2: 4.640).
CONCLUSION
Radiological findings can predict the long-term pulmonary sequelae of COVID-19 patients. CTSS is an important predictor of lung fibrosis and COVID-19 mortality. Lung fibrosis can be diagnosed and tracked using the LUS. Changes in RALE score during hospitalization can be used as an independent predictor of mortality.
Topics: Humans; Male; Female; COVID-19; SARS-CoV-2; Pulmonary Fibrosis; Respiratory Sounds; Lung; Disease Progression
PubMed: 37491177
DOI: 10.1016/j.acra.2023.06.002 -
Current Opinion in Virology Jun 2024Respiratory viral infections represent a constant threat for human health and urge for a better understanding of the pulmonary immune response to prevent disease... (Review)
Review
Respiratory viral infections represent a constant threat for human health and urge for a better understanding of the pulmonary immune response to prevent disease severity. Macrophages are at the center of pulmonary immunity, where they play a pivotal role in orchestrating beneficial and/or pathological outcomes during infection. Eicosanoids, the host bioactive lipid mediators, have re-emerged as important regulators of pulmonary immunity during respiratory viral infections. In this review, we summarize the current knowledge linking eicosanoids' and pulmonary macrophages' homeostatic and antimicrobial functions and discuss eicosanoids as emerging targets for immunotherapy in viral infection.
Topics: Eicosanoids; Humans; Macrophages, Alveolar; Animals; Lung; Virus Diseases; Respiratory Tract Infections
PubMed: 38547562
DOI: 10.1016/j.coviro.2024.101399 -
QJM : Monthly Journal of the... Jul 2023Pulmonary fibrosis is a sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that currently lacks effective preventative or therapeutic... (Review)
Review
Pulmonary fibrosis is a sequelae of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection that currently lacks effective preventative or therapeutic measures. Post-viral lung fibrosis due to SARS-CoV-2 has been shown to be progressive on selected patients using imaging studies. Persistent infiltration of macrophages and monocytes, a main feature of SARS-CoV-2 pulmonary fibrosis, and long-lived circulating inflammatory monocytes might be driving factors promoting the profibrotic milieu in the lung. The upstream signal(s) that regulates the presence of these immune cells (despite complete viral clearance) remains to be explored. Current data indicate that much of the stimulating signals are localized in the lungs. However, an ongoing low-grade systemic inflammation in long Coronavirus Disease 2019 (COVID-19) symptoms suggests that certain non-pulmonary regulators such as epigenetic changes in hematopoietic stem cells might be critical to the chronic inflammatory response. Since nearly one-third of the world population have been infected, a timely understanding of the underlying pathogenesis leading to tissue remodeling is required. Herein, we review the potential pathogenic mechanisms driving lung fibrosis following SARS-CoV-2 infection based upon available studies and our preliminary findings (Graphical abstract).
Topics: Humans; Pulmonary Fibrosis; COVID-19; SARS-CoV-2; Lung; Inflammation
PubMed: 36018274
DOI: 10.1093/qjmed/hcac206 -
Frontiers in Cellular and Infection... 2023Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved... (Review)
Review
Non-tuberculous mycobacteria (NTM) are opportunistic pathogens that can infect all body tissues and organs. In particular, the lungs are the most commonly involved organ, with NTM pulmonary diseases causing serious health issues in patients with underlying lung disease. Moreover, NTM infections have been steadily increasing worldwide in recent years. NTM are also naturally resistant to many antibiotics, specifically anti-tuberculosis (anti-TB) drugs. The lack of drugs targeting NTM infections and the increasing drug resistance of NTM have further made treating these mycobacterial diseases extremely difficult. The currently recommended NTM treatments rely on the extended indications of existing drugs, which underlines the difficulties of new antibiotic discovery against NTM. Another challenge is determining which drug combinations are most effective against NTM infection. To a certain extent, anti-NTM drug development depends on using already available antibiotics and compounds. Here, we aimed to review new antibiotics or compounds with good antibacterial activity against NTM, focusing on their mechanisms of action, and antibacterial activities.
Topics: Humans; Nontuberculous Mycobacteria; Mycobacterium Infections, Nontuberculous; Lung Diseases; Antitubercular Agents; Lung
PubMed: 37850054
DOI: 10.3389/fcimb.2023.1243457 -
Viruses Apr 2024Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV...
Reactivation and infection with cytomegalovirus (CMV) are frequently observed in recipients of solid organ transplants, bone marrow transplants, and individuals with HIV infection. This presents an increasing risk of allograft rejection, opportunistic infection, graft failure, and patient mortality. Among immunocompromised hosts, interstitial pneumonia is the most critical clinical manifestation of CMV infection. Recent studies have demonstrated the potential therapeutic benefits of exosomes derived from mesenchymal stem cells (MSC-exos) in preclinical models of acute lung injury, including pneumonia, ARDS, and sepsis. However, the role of MSC-exos in the pathogenesis of infectious viral diseases, such as CMV pneumonia, remains unclear. In a mouse model of murine CMV-induced pneumonia, we observed that intravenous administration of mouse MSC (mMSC)-exos reduced lung damage, decreased the hyperinflammatory response, and shifted macrophage polarization from the M1 to the M2 phenotype. Treatment with mMSC-exos also significantly reduced the infiltration of inflammatory cells and pulmonary fibrosis. Furthermore, in vitro studies revealed that mMSC-exos reversed the hyperinflammatory phenotype of bone marrow-derived macrophages infected with murine CMV. Mechanistically, mMSC-exos treatment decreased activation of the NF-κB/NLRP3 signaling pathway both in vivo and in vitro. In summary, our findings indicate that mMSC-exo treatment is effective in severe CMV pneumonia by reducing lung inflammation and fibrosis through the NF-κB/NLRP3 signaling pathway, thus providing promising therapeutic potential for clinical CMV infection.
Topics: Animals; Exosomes; Mesenchymal Stem Cells; Mice; NLR Family, Pyrin Domain-Containing 3 Protein; NF-kappa B; Signal Transduction; Muromegalovirus; Disease Models, Animal; Mice, Inbred C57BL; Macrophages; Cytomegalovirus Infections; Lung; Pneumonia, Viral; Herpesviridae Infections; Pneumonia
PubMed: 38675960
DOI: 10.3390/v16040619 -
Emerging Infectious Diseases Nov 2023We report a rare case of aorto-bi-iliac prosthetic allograft mucormycosis in a 57-year-old immunocompetent patient in France. Outcome was favorable after surgery and... (Review)
Review
We report a rare case of aorto-bi-iliac prosthetic allograft mucormycosis in a 57-year-old immunocompetent patient in France. Outcome was favorable after surgery and dual antifungal therapy with liposomal amphotericin B and isavuconazole. In a literature review, we identified 12 other cases of prosthetic vascular or heart valve mucormycosis; mortality rate was 38%.
Topics: Humans; Middle Aged; Mucormycosis; Antifungal Agents; Rhizopus; Transplantation, Homologous; Lung
PubMed: 37877713
DOI: 10.3201/eid2911.230837 -
The Journal of Clinical Investigation Oct 2023Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune...
Lung inflammation is a hallmark of Coronavirus disease 2019 (COVID-19) in patients who are severely ill, and the pathophysiology of disease is thought to be immune mediated. Mast cells (MCs) are polyfunctional immune cells present in the airways, where they respond to certain viruses and allergens and often promote inflammation. We observed widespread degranulation of MCs during acute and unresolved airway inflammation in SARS-CoV-2-infected mice and nonhuman primates. Using a mouse model of MC deficiency, MC-dependent interstitial pneumonitis, hemorrhaging, and edema in the lung were observed during SARS-CoV-2 infection. In humans, transcriptional changes in patients requiring oxygen supplementation also implicated cells with a MC phenotype in severe disease. MC activation in humans was confirmed through detection of MC-specific proteases, including chymase, the levels of which were significantly correlated with disease severity and with biomarkers of vascular dysregulation. These results support the involvement of MCs in lung tissue damage during SARS-CoV-2 infection in animal models and the association of MC activation with severe COVID-19 in humans, suggesting potential strategies for intervention.
Topics: Humans; Animals; COVID-19; Mast Cells; SARS-CoV-2; Lung; Inflammation
PubMed: 37561585
DOI: 10.1172/JCI149834 -
Saudi Medical Journal Jan 2024To analyze the influence of pulmonary infection after radical esophagectomy on serum inflammatory markers, pulmonary function, and prognosis.
OBJECTIVES
To analyze the influence of pulmonary infection after radical esophagectomy on serum inflammatory markers, pulmonary function, and prognosis.
METHODS
We enrolled 278 esophageal cancer patients who underwent radical esophagectomy. Patients were split into the infected (n=51) and uninfected groups (n=227). The inflammatory parameters, complications, and prognosis were compared.
RESULTS
In the infected group, interleukin (IL)-6 was 16.19±2.63 ng/L, tumor necrosis factor-α was 19.64±3.07 µg/L, and IL-1β was 22.49±5.13 ng/L at 7 days postoperatively; white blood cell counts was 12.65±2.14 ×10/L, percentage of neutrophils (NEU%) was 67.04±10.48%, and platelet (PLT) counts was 249.82±63.26 ×10/L; the increasing ranges of the above factors after the operation were much raised compared with the uninfected group (<0.05). Compared with the uninfected group, forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and FEV1/FVC were greater declines in ranges (<0.05), and the arrhythmia incidence and the mortality within 60 days postoperatively were greater in the infected group (<0.05).
CONCLUSION
Postoperative pulmonary infection can lead to pulmonary function damage, proinflammatory factor overexpression, and an increased risk of early death.
Topics: Humans; Esophagectomy; Lung; Prognosis; Biomarkers; Pneumonia; Postoperative Complications; Interleukin-6; Forced Expiratory Volume
PubMed: 38220231
DOI: 10.15537/smj.2024.45.1.20230504