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Journal of Thoracic Oncology : Official... Jul 2023Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors...
INTRODUCTION
Severe pulmonary hemorrhage can occur in patients treated with thoracic stereotactic ablative radiotherapy (SABR) and vascular endothelial growth factor inhibitors (VEGFis). There is limited understanding of which patients are at risk for toxicity with the combination of thoracic SABR and VEGFis or how the risk differs over either therapy alone.
METHODS
We evaluated a prospectively maintained cohort of 690 patients with 818 pulmonary tumors treated with highly conformal SABR. Rates of any-grade and grade 3 plus (G3+) pulmonary hemorrhage were compared between patients treated with or without VEGFi therapy across tumor locations. Outcomes were compared between patients treated with SABR plus VEGFi and a propensity-matched cohort of those treated with VEGFi therapy alone.
RESULTS
Treatment with VEGFi plus SABR was associated with higher rates of G3+ pulmonary hemorrhage compared with those treated with SABR alone for the overall cohort (3-y incidence: 7.9% versus 0.6%, p < 0.01) and those with central tumors (19.1% versus 3.3%, p = 0.04). When further subdivided, there were significantly higher toxicity rates with VEGFi for the ultracentral (9.0% versus 45.0%, p = 0.044), but not central nonabutting tumors (0.0% versus 1.3%, p = 0.69). There was an increased incidence of G3+ hemorrhage in patients treated with VEGFi plus SABR compared with VEGFi alone (9.6% versus 1.3%, p = 0.04).
CONCLUSIONS
The combination of VEGFi and SABR was associated with an increased risk of high-grade pulmonary hemorrhage over either therapy alone. Low rates of toxicity were observed when excluding patients with SABR to ultracentral tumors and applying highly conformal SABR techniques.
Topics: Humans; Lung Neoplasms; Angiogenesis Inhibitors; Vascular Endothelial Growth Factor A; Radiosurgery; Hemorrhage
PubMed: 37085030
DOI: 10.1016/j.jtho.2023.04.007 -
The Journal of Clinical Investigation Aug 2023Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies...
Exaggerated Type 2 immune responses play critical roles in the pathogenesis of a variety of diseases including asthma, allergy, and pulmonary fibrosis. Recent studies have highlighted the importance of innate type 2 immune responses and innate lymphoid 2 cells (ILC2s) in these disorders. However, the mechanisms that control the development of pulmonary innate type 2 responses (IT2IR) and the recruitment and/or activation of ILC2 cells are poorly understood. In mouse models of pulmonary IT2IR, we demonstrated that phospholipid scramblase-1 (PLSCR1), a type II transmembrane protein that mediates bidirectional and nonspecific translocation of phospholipids between the inner and outer leaflets of the plasma membrane, was a critical regulator of IT2IR in the lung. We further suggested that (a) PLSCR1 bound to and physically interacted with chemoattractant receptor-homologous molecule(CRTH2), which is a G-protein-coupled receptor that is expressed on TH2 cells and on multiple immune cells and is commonly used to identify ILC2 cells, and (b) the effects of PLSCR1 on ILC2 activation and IT2IR were mediated via CRTH2-dependent mechanisms. Overall, our studies demonstrated that PLSCR1 played an essential role in the pathogenesis of ILC2 responses, providing critical insights into biology and disease pathogenesis and identifying targets that can be manipulated in attempts to control IT2IR in chronic diseases such as asthma.
Topics: Animals; Mice; Immunity, Innate; Phospholipid Transfer Proteins; Lymphocytes; Inflammation; Asthma; Lung; Cytokines
PubMed: 37289545
DOI: 10.1172/JCI169583 -
Nature Communications Aug 2023Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here...
Biomaterial scaffolds mimicking the environment in metastatic organs can deconstruct complex signals and facilitate the study of cancer progression and metastasis. Here we report that a subcutaneous scaffold implant in mouse models of metastatic breast cancer in female mice recruits lung-tropic circulating tumor cells yet suppresses their growth through potent in situ antitumor immunity. In contrast, the lung, the endogenous metastatic organ for these models, develops lethal metastases in aggressive breast cancer, with less aggressive tumor models developing dormant lungs suppressing tumor growth. Our study reveals multifaceted roles of neutrophils in regulating metastasis. Breast cancer-educated neutrophils infiltrate the scaffold implants and lungs, secreting the same signal to attract lung-tropic circulating tumor cells. Second, antitumor and pro-tumor neutrophils are selectively recruited to the dormant scaffolds and lungs, respectively, responding to distinct groups of chemoattractants to establish activated or suppressive immune environments that direct different fates of cancer cells.
Topics: Female; Animals; Mice; Neutrophils; Lung Neoplasms; Neoplastic Cells, Circulating; Lung; Biocompatible Materials; Cell Line, Tumor; Neoplasm Metastasis; Tumor Microenvironment
PubMed: 37553342
DOI: 10.1038/s41467-023-40478-5 -
Pediatric Radiology Apr 2024Pediatric lung infections continue to be a leading cause of pediatric morbidity and mortality. Although both pediatric and general radiologists are familiar with typical... (Review)
Review
Pediatric lung infections continue to be a leading cause of pediatric morbidity and mortality. Although both pediatric and general radiologists are familiar with typical lung infections and their imaging findings in children, relatively rare lung infections continue to present a diagnostic challenge. In addition, the advances in radiological imaging and emergence of several new lung infections in recent years facilitated the need for up-to-date knowledge on this topic. In this review article, we discuss the imaging findings of pediatric lung infections caused by unusual/uncommon and new pathogens. We review the epidemiological, clinical, and radiological imaging findings of viral (coronavirus disease 2019, Middle East respiratory syndrome, bird flu), bacterial (Streptococcus anginosus, Francisella tularensis, Chlamydia psittaci), and parasitic lung infections (echinococcosis, paragonimiasis, amoebiasis). Additional disorders whose clinical course and imaging findings may mimic lung infections in children (hypersensitivity pneumonitis, pulmonary hemorrhage, eosinophilic pneumonia) are also presented, to aid in differential diagnosis. As the clinical presentation of children with new and unusual lung infections is often non-specific, imaging evaluation plays an important role in initial detection, follow-up for disease progression, and assessment of potential complications.
Topics: Child; Humans; Lung; Pneumonia; COVID-19; Lung Diseases; Thorax
PubMed: 38097820
DOI: 10.1007/s00247-023-05818-z -
Nature Communications Jul 2023CD8 T cell tissue resident memory (T) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived....
CD8 T cell tissue resident memory (T) cells are especially suited to control pathogen spread at mucosal sites. However, their maintenance in lung is short-lived. TCR-dependent NFkB signaling is crucial for T cell memory but how and when NFkB signaling modulates tissue resident and circulating T cell memory during the immune response is unknown. Here, we find that enhancing NFkB signaling in T cells once memory to influenza is established, increases pro-survival Bcl-2 and CD122 levels thus boosting lung CD8 T maintenance. By contrast, enhancing NFkB signals during the contraction phase of the response leads to a defect in CD8 T differentiation without impairing recirculating memory subsets. Specifically, inducible activation of NFkB via constitutive active IKK2 or TNF interferes with TGFβ signaling, resulting in defects of lung CD8 T imprinting molecules CD69, CD103, Runx3 and Eomes. Conversely, inhibiting NFkB signals not only recovers but improves the transcriptional signature and generation of lung CD8 T. Thus, NFkB signaling is a critical regulator of tissue resident memory, whose levels can be tuned at specific times during infection to boost lung CD8 T.
Topics: Humans; Influenza, Human; Immunologic Memory; CD8-Positive T-Lymphocytes; Lung; Signal Transduction; NF-kappa B
PubMed: 37468506
DOI: 10.1038/s41467-023-40107-1 -
Short-range interactions between fibrocytes and CD8 T cells in COPD bronchial inflammatory response.ELife Jul 2023Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells....
Bronchi of chronic obstructive pulmonary disease (COPD) are the site of extensive cell infiltration, allowing persistent contact between resident cells and immune cells. Tissue fibrocytes interaction with CD8 T cells and its consequences were investigated using a combination of , experiments and mathematical modeling. We show that fibrocytes and CD8 T cells are found in the vicinity of distal airways and that potential interactions are more frequent in tissues from COPD patients compared to those of control subjects. Increased proximity and clusterization between CD8 T cells and fibrocytes are associated with altered lung function. Tissular CD8 T cells from COPD patients promote fibrocyte chemotaxis via the CXCL8-CXCR1/2 axis. Live imaging shows that CD8 T cells establish short-term interactions with fibrocytes, that trigger CD8 T cell proliferation in a CD54- and CD86-dependent manner, pro-inflammatory cytokines production, CD8 T cell cytotoxic activity against bronchial epithelial cells and fibrocyte immunomodulatory properties. We defined a computational model describing these intercellular interactions and calibrated the parameters based on our experimental measurements. We show the model's ability to reproduce histological ex vivo characteristics, and observe an important contribution of fibrocyte-mediated CD8 T cell proliferation in COPD development. Using the model to test therapeutic scenarios, we predict a recovery time of several years, and the failure of targeting chemotaxis or interacting processes. Altogether, our study reveals that local interactions between fibrocytes and CD8 T cells could jeopardize the balance between protective immunity and chronic inflammation in the bronchi of COPD patients.
Topics: Humans; CD8-Positive T-Lymphocytes; Pulmonary Disease, Chronic Obstructive; Bronchi; Epithelial Cells; Inflammation
PubMed: 37494277
DOI: 10.7554/eLife.85875 -
Nature Immunology Jan 2024
Topics: Lung; CD8-Positive T-Lymphocytes; Immunologic Memory
PubMed: 38168965
DOI: 10.1038/s41590-023-01728-2 -
Cellular & Molecular Immunology Nov 2023Aeroallergen sensitization, mainly mediated by lung epithelium and dendritic cells (DCs), is integral to allergic asthma pathogenesis and progression. IL-10 has a dual...
Aeroallergen sensitization, mainly mediated by lung epithelium and dendritic cells (DCs), is integral to allergic asthma pathogenesis and progression. IL-10 has a dual role in immune responses, as it inhibits myeloid cell activation but promotes B-cell responses and epithelial cell proliferation. Here, we report a proinflammatory function of B-cell-derived IL-10 modulated by Bcl-3 in allergic asthma. Specifically, Bcl-3 mice showed elevated IL-10 levels and were found to be highly vulnerable to allergic asthma induced by house dust mites (HDMs). IL-10 had a positive correlation with the levels of the DC chemoattractant CCL-20 in HDM-sensitized mice and in patients with asthma and induced a selective increase in CCL-20 production by mouse lung epithelial cells. Blockade of IL-10 or IL-10 receptors during sensitization dampened both HDM-induced sensitization and asthma development. IL-10 levels peaked 4 h post sensitization with HDM and IL-10 was primarily produced by B cells under Bcl-3-Blimp-1-Bcl-6 regulation. Mice lacking B-cell-derived IL-10 displayed decreased lung epithelial CCL-20 production and diminished DC recruitment to the lungs upon HDM sensitization, thereby demonstrating resistance to HDM-induced asthma. Moreover, responses to HDM stimulation in Bcl-3 mice lacking B-cell-derived IL-10 were comparable to those in Bcl-3 mice. The results revealed an unexpected role of B-cell-derived IL-10 in promoting allergic sensitization and demonstrated that Bcl-3 prevents HDM-induced asthma by inhibiting B-cell-derived IL-10 production. Thus, targeting the Bcl-3/IL-10 axis to inhibit allergic sensitization is a promising approach for treating allergic asthma. IL-10 is released rapidly from lung plasma cells under Bcl-3-Blimp-1-Bcl-6 regulation upon house dust mite exposure and amplifies lung epithelial cell (EC)-derived CCL-20 production and subsequent dendritic cell (DC) recruitment to promote allergic sensitization in asthma.
Topics: Animals; Humans; Mice; Allergens; Asthma; Dendritic Cells; Disease Models, Animal; Interleukin-10; Lung; Pyroglyphidae; Th2 Cells
PubMed: 37653127
DOI: 10.1038/s41423-023-01079-w -
In Vivo (Athens, Greece) 2023Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain...
BACKGROUND/AIM
Gaucher disease (GD) is a rare lysosomal storage disorder that can involve the lungs and pulmonary vasculature. The long-term effects of GD on respiratory health remain unclear due to limited data on the natural history of this disease. We analyzed electronic health records for 11,004 patients with GD over 10-20 years to determine the incidence of pulmonary hypertension (PH), lung disease, and other respiratory comorbidities and better understand disease course to guide management.
PATIENTS AND METHODS
We conducted a retrospective cohort study using the TriNetX research database of 130 million international patients. The incidence of primary/secondary PH, pulmonary heart disease, interstitial/obstructive/restrictive lung disease, pulmonary hemorrhage, and pulmonary embolism was assessed in patients with GD from 2000-2020.
RESULTS
Incidence rates of all conditions assessed increased from 10 to 20 years of follow-up. Excess risk of PH, lung disease, and pulmonary hemorrhage was significantly higher in GD patients after 20 versus 10 years.
CONCLUSION
Extended follow-up in GD is associated with substantially higher risks of PH, lung disease and other respiratory comorbidities, highlighting the need for close monitoring and early intervention to mitigate long-term pulmonary decline. Improved understanding of mechanisms driving respiratory deterioration can support the development of novel treatments to optimize outcomes in this population at high risk of pulmonary morbidity and mortality.
Topics: Humans; Gaucher Disease; Incidence; Retrospective Studies; Lung; Lung Diseases; Cohort Studies; Hemorrhage
PubMed: 37652520
DOI: 10.21873/invivo.13330 -
Blood Advances Aug 2023Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have...
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) enters the respiratory tract, where it infects the alveoli epithelial lining. However, patients have sequelae that extend well beyond the alveoli into the pulmonary vasculature and, perhaps, beyond to the brain and other organs. Because of the dynamic events within blood vessels, histology does not report platelet and neutrophil behavior. Because of the rapid nontranscriptional response of these cells, neither single-cell RNA sequencing nor proteomics report robustly on their critical behaviors. We used intravital microscopy in level-3 containment to examine the pathogenesis of SARS-CoV-2 within 3 organs in mice expressing human angiotensin converting enzyme 2 (ACE-2) ubiquitously (CAG-AC-70) or on epithelium (K18-promoter). Using a neon-green SARS-CoV-2, we observed both the epithelium and endothelium infected in AC70 mice but only the epithelium in K18 mice. There were increased neutrophils in the microcirculation but not in the alveoli of the lungs of AC70 mice. Platelets formed large aggregates in the pulmonary capillaries. Despite only neurons being infected within the brain, profound neutrophil adhesion forming the nidus of large platelet aggregates were observed in the cerebral microcirculation, with many nonperfused microvessels. Neutrophils breached the brain endothelial layer associated with a significant disruption of the blood-brain-barrier. Despite ubiquitous ACE-2 expression, CAG-AC-70 mice had very small increases in blood cytokine, no increase in thrombin, no infected circulating cells, and no liver involvement suggesting limited systemic effects. In summary, our imaging of SARS-CoV-2-infected mice gave direct evidence that there is a significant perturbation locally in the lung and brain microcirculation induced by local viral infection leading to increased local inflammation and thrombosis in these organs.
Topics: Animals; Mice; COVID-19; Inflammation; Lung; SARS-CoV-2
PubMed: 37307197
DOI: 10.1182/bloodadvances.2022009430