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In the temperate regions, seasonal influenza virus outbreaks correlate closely with decreases in humidity. While low ambient humidity is known to enhance viral transmission, its impact on host response to influenza virus infection and disease outcome remains unclear. Here, we showed that housing Mx1 congenic mice in low relative humidity makes mice more susceptible to severe disease following respiratory challenge with influenza A virus. We find that inhalation of dry air impairs mucociliary clearance, innate antiviral defense, and tissue repair. Moreover, disease exacerbated by low relative humidity was ameliorated in caspase-1/11–deficient Mx1 mice, independent of viral burden. Single-cell RNA sequencing revealed that induction of IFN-stimulated genes in response to viral infection was diminished in multiple cell types in the lung of mice housed in low humidity condition. These results indicate that exposure to dry air impairs host defense against influenza infection, reduces tissue repair, and inflicts caspase-dependent disease pathology.

Secondary bacterial pneumonia leads to increased morbidity and mortality from influenza virus infections. What causes this increased susceptibility, however, is not well defined. Host defense from infection relies not only on immune resistance mechanisms but also on the ability to tolerate a given level of pathogen burden. Failure of either resistance or tolerance can contribute to disease severity, making it hard to distinguish their relative contribution. We employ a coinfection mouse model of influenza virus and Legionella pneumophila in which we can separate resistance and tolerance. We demonstrate that influenza virus can promote susceptibility to lethal bacterial coinfection, even when bacterial infection is controlled by the immune system. We propose that this failure of host defense is due to impaired ability to tolerate tissue damage.

Thyroid hormone improves mitochondrial function and dynamics in lung epithelium to reduce pulmonary fibrosis in mice. Thyroid hormone (TH) is critical for the maintenance of cellular homeostasis during stress responses, but its role in lung fibrosis is unknown. Here we found that the activity and expression of iodothyronine deiodinase 2 (DIO2), an enzyme that activates TH, were higher in lungs from patients with idiopathic pulmonary fibrosis than in control individuals and were correlated with disease severity. We also found that Dio2 -knockout mice exhibited enhanced bleomycin-induced lung fibrosis. Aerosolized TH delivery increased survival and resolved fibrosis in two models of pulmonary fibrosis in mice (intratracheal bleomycin and inducible TGF-β1). Sobetirome, a TH mimetic, also blunted bleomycin-induced lung fibrosis. After bleomycin-induced injury, TH promoted mitochondrial biogenesis, improved mitochondrial bioenergetics and attenuated mitochondria-regulated apoptosis in alveolar epithelial cells both in vivo and in vitro . TH did not blunt fibrosis in Ppargc1a - or Pink1 -knockout mice, suggesting dependence on these pathways. We conclude that the antifibrotic properties of TH are associated with protection of alveolar epithelial cells and restoration of mitochondrial function and that TH may thus represent a potential therapy for pulmonary fibrosis.

Influenza A virus (IAV) causes up to half a million deaths worldwide annually, 90% of which occur in older adults. We show that IAV-infected monocytes from older humans have impaired antiviral interferon production but retain intact inflammasome responses. To understand the in vivo consequence, we used mice expressing a functional Mx gene encoding a major interferon-induced effector against IAV in humans. In Mx1-intact mice with weakened resistance due to deficiencies in Mavs and TIr7, we found an elevated respiratory bacterial burden. Notably, mortality in the absence of Mavs and TIr7 was independent of viral load or MyD88-dependent signaling but dependent on bacterial burden, caspase-1/11, and neutrophil-dependent tissue damage. Therefore, in the context of weakened antiviral resistance, vulnerability to IAV disease is a function of caspase-dependent pathology.

A long-standing problem in lung cancer pathology has been to determine whether two anatomically distinct foci of lung carcinoma are independent primaries or intrapulmonary metastases. While several proposals exist with respect to this problem, it is not known how pathologists use these proposals in actual practice. We performed a voluntary survey of the Pulmonary Pathology Society, a self-selected group of pathologists with a specialty interest in pulmonary pathology, to determine their opinion on staging various specific scenarios of multiple foci of lung cancer. We found that there was a great deal of disagreement and uncertainty in the approach to these scenarios unless there were also unambiguous molecular markers or a dramatic difference in histology. Pathologists have a high degree of uncertainty and disagreement on staging multiple lung carcinomas. An improved pathologic method is required to distinguish separate primary tumors from intrapulmonary metastases. Until that is available, improved nomenclature is needed to convey the intrinsic uncertainty of the situation.

Myasthenia gravis (MG) is a neuromuscular, autoimmune disease caused by autoantibodies that target postsynaptic proteins, primarily the acetylcholine receptor (AChR) and inhibit signaling at the neuromuscular junction. The majority of patients under 50 y with AChR autoantibody MG have thymic lymphofollicular hyperplasia. The MG thymus is a reservoir of plasma cells that secrete disease-causing AChR autoantibodies and although thymectomy improves clinical scores, many patients fail to achieve complete stable remission without additional immunosuppressive treatments. We speculate that thymus-associated B cells and plasma cells persist in the circulation after thymectomy and that their persistence could explain incomplete responses to resection. We studied patients enrolled in a randomized clinical trial and used complementary modalities of B cell repertoire sequencing to characterize the thymus B cell repertoire and identify B cell clones that resided in the thymus and circulation before and 12 mo after thymectomy. Thymus-associated B cell clones were detected in the circulation by both mRNA-based and genomic DNA-based sequencing. These antigen-experienced B cells persisted in the circulation after thymectomy. Many circulating thymus-associated B cell clones were inferred to have originated and initially matured in the thymus before emigration from the thymus to the circulation. The persistence of thymus-associated B cells correlated with less favorable changes in clinical symptom measures, steroid dose required to manage symptoms, and marginal changes in AChR autoantibody titer. This investigation indicates that the diminished clinical response to thymectomy is related to persistent circulating thymus-associated B cell clones.

Sarcoidosis is an idiopathic inflammatory disorder that is commonly treated with glucocorticoids. An imprecise understanding of the immunologic changes underlying sarcoidosis has limited therapeutic progress. Here in this open-label trial (NCT03910543), 10 patients with cutaneous sarcoidosis are treated with tofacitinib, a Janus kinase inhibitor. The primary outcome is the change in the cutaneous sarcoidosis activity and morphology instrument (CSAMI) activity score after 6 months of treatment. Secondary outcomes included change in internal organ involvement, molecular parameters, and safety. All patients experience improvement in their skin with 6 patients showing a complete response. Improvement in internal organ involvement is also observed. CD4 + T cell-derived IFN-γ is identified as a central cytokine mediator of macrophage activation in sarcoidosis. Additional type 1 cytokines produced by distinct cell types, including IL-6, IL-12, IL-15 and GM-CSF, also associate with pathogenesis. Suppression of the activity of these cytokines, especially IFN-γ, correlates with clinical improvement. Our results thus show that tofacitinib treatment is associated with improved sarcoidosis symptoms, and predominantly acts by inhibiting type 1 immunity. Sarcoidosis is a heterogenous disorder often treated with glucocorticoids. Here the authors show, in an open label, non-randomized, single arm clinical trial involving 10 patients, that treatment with tofacitinib, a Janus kinase inhibitor, is associated with improved clinical symptoms and reduced activity of Th1 cytokines such as IFN-γ and IL-12.

Abstract Objectives The aim of this study was to devise reproducible biopsy criteria for distinguishing pulmonary large cell neuroendocrine carcinoma (LCNEC) from non-small cell lung carcinoma (NSCLC). Methods Tissue microarrays of LCNEC and NSCLC were generated from resection specimens and used as biopsy surrogates. They were stained for neuroendocrine markers, Ki-67, napsin-A, and p40, and independently analyzed by standardized morphologic criteria by four pathologists. Tumors were scored based on morphology, neuroendocrine marker expression, and Ki-67 proliferative index. Results The average total score for LCNEC was significantly higher than for NSCLC (5.65 vs 0.51, P < .0001). Utilizing a cutoff score of 4 or higher showed 100% sensitivity and 99% specificity for LCNEC diagnosis, with an excellent agreement among four pathologists (98%). Conclusions The proposed semiquantitative approach based on a combination of specific morphologic and immunophenotypic features may be a useful tool for biopsy diagnosis of LCNEC.

Objectives: The aim of this study was to devise reproducible biopsy criteria for distinguishing pulmonary large cell neuroendocrine carcinoma (LCNEC) from non-small cell lung carcinoma (NSCLC). Methods: Tissue microarrays of LCNEC and NSCLC were generated from resection specimens and used as biopsy surrogates. They were stained for neuroendocrine markers, Ki-67, napsin-A, andp40, and independently analyzed by standardized morphologic criteria by four pathologists. Tumors were scored based on morphology, neuroendocrine marker expression, and Ki-67 proliferative index. Results: The average total score for LCNEC was significantly higher than for NSCLC (5.65 vs 0.51, P < .0001). Utilizing a cutoff score of 4 or higher showed 100% sensitivity and 99% specificity for LCNEC diagnosis, with an excellent agreement among four pathologists (98%). Conclusions: The proposed semiquantitative approach based on a combination of specific morphologic and immunophenotypic features may be a useful tool for biopsy diagnosis of LCNEC. Key Words: Large cell neuroendocrine carcinoma of the lung; Biopsy diagnosis; Scoring criteria

Administration of supplemental oxygen remains a critical clinical intervention for survival of preterm infants with respiratory failure. However, prolonged exposure to hyperoxia can augment pulmonary damage, resulting in developmental lung diseases embodied as hyperoxia-induced acute lung injury and bronchopulmonary dysplasia (BPD). We sought to investigate the role of autophagy in hyperoxia-induced apoptotic cell death in developing lungs. We identified increased autophagy signaling in hyperoxia-exposed mouse lung epithelial-12 cells, freshly isolated fetal type II alveolar epithelial cells, lungs of newborn wild-type mice, and human newborns with respiratory distress syndrome and evolving and established BPD. We found that hyperoxia exposure induces autophagy in a Trp53-dependent manner in mouse lung epithelial-12 cells and in neonatal mouse lungs. Using pharmacological inhibitors and gene silencing techniques, we found that the activation of autophagy, upon hyperoxia exposure, demonstrated a protective role with an antiapoptotic response. Specifically, inhibiting regulatory-associated protein of mechanistic target of rapamycin (RPTOR) in hyperoxia settings, as evidenced by wild-type mice treated with torin2 or mice administered (Rptor) silencing RNA via intranasal delivery or Rptor , limited lung injury by increased autophagy, decreased apoptosis, improved lung architecture, and increased survival. Furthermore, we identified increased protein expression of phospho-beclin1, light chain-3-II and lysosomal-associated membrane protein 1, suggesting altered autophagic flux in the lungs of human neonates with established BPD. Collectively, our study unveils a novel demonstration of enhancing autophagy and antiapoptotic effects, specifically through the inhibition of RPTOR as a potentially useful therapeutic target for the treatment of hyperoxia-induced acute lung injury and BPD in developing lungs.