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The lymphatic vasculature is critical for lung function, but defects in lymphatic function in the pathogenesis of lung disease is understudied. In mice, lymphatic dysfunction alone is sufficient to cause lung injury that resembles human emphysema. Whether lymphatic function is disrupted in cigarette smoke (CS)-induced emphysema is unknown. In this study, we investigated lung lymphatic function in the pathogenesis of CS-induced emphysema. Analysis of human lung tissue revealed significant lung lymphatic thrombosis in patients with emphysema compared to control smokers that increased with disease severity. In vitro assays demonstrated a direct effect of CS on lymphatic endothelial cell integrity. In a mouse model, CS exposure led to lung lymphatic thrombosis, decreased lymphatic drainage, and impaired leukocyte trafficking that preceded emphysema. Proteomic analysis of lymph confirmed upregulation of coagulation and inflammatory pathways in the lymphatics of CS-exposed mice compared to control mice. These data suggest that CS exposure results in lung lymphatic dysfunction with thrombosis, impaired leukocyte trafficking, and changes in the composition of lymph. In patients with emphysema, lung lymphatic thrombosis is seen with increasing disease severity. These studies for the first time demonstrate lung lymphatic dysfunction after cigarette smoke exposure and suggest a novel component in the pathogenesis of emphysema.

The novel coronavirus disease-19 (COVID-19) pandemic caused by SARS-CoV-2 has ravaged global healthcare with previously unseen levels of morbidity and mortality. To date, methods to predict the clinical course, which ranges from the asymptomatic carrier to the critically ill patient in devastating multi-system organ failure, have yet to be identified. In this study, we performed large-scale integrative multi-omics analyses of serum obtained from COVID-19 patients with the goal of uncovering novel pathogenic complexities of this disease and identifying molecular signatures that predict clinical outcomes. We assembled a novel network of protein-metabolite interactions in COVID-19 patients through targeted metabolomic and proteomic profiling of serum samples in 330 COVID-19 patients compared to 97 non-COVID, hospitalized controls. Our network identified distinct protein-metabolite cross talk related to immune modulation, energy and nucleotide metabolism, vascular homeostasis, and collagen catabolism. Additionally, our data linked multiple proteins and metabolites to clinical indices associated with long-term mortality and morbidity, such as acute kidney injury. Finally, we developed a novel composite outcome measure for COVID-19 disease severity and created a clinical prediction model using a set of 33 metabolites. The model significantly improved the identification of key events of critical illness such as prolonged hospitalization, supplemental oxygen requirement, acute kidney injury (AKI), and acute respiratory distress syndrome (ARDS), beyond those achieved using the more traditional risk factors of age, gender, and BMI.

Vascular injury is a menacing element of acute respiratory distress syndrome (ARDS) pathogenesis. To better understand the role of vascular injury in COVID-19 ARDS, we used lung autopsy immunohistochemistry and blood proteomics from COVID-19 subjects at distinct timepoints in disease pathogenesis, including a hospitalized cohort at risk of ARDS development (“at risk”, N=59), an intensive care unit cohort with ARDS (“ARDS”, N=31), and a cohort recovering from ARDS (“recovery”, N=12). COVID-19 ARDS lung autopsy tissue revealed an association between vascular injury and platelet-rich microthrombi. This link guided the derivation of a protein signature in the at risk cohort characterized by lower expression of vascular proteins in subjects who died, an early signal of vascular limitation termed the maladaptive vascular response. These findings were replicated in COVID-19 ARDS subjects, as well as when bacterial and influenza ARDS patients (N=29) were considered, hinting at a common final pathway of vascular injury that is more disease (ARDS) then cause (COVID-19) specific, and may be related to vascular cell death. Among recovery subjects, our vascular signature identified patients with good functional recovery one year later. This vascular injury signature could be used to identify ARDS patients most likely to benefit from vascular targeted therapies.

COVID-19 outcomes like mortality have been associated with albumin alteration. However, it is unclear whether albumin changes in COVID-19 are pathogen specific or not. To this end, we characterized the kinetics of serum albumin in mechanically ventilated patients with COVID-19 compared to mechanically ventilated patients with sepsis-induced Acute Respiratory Distress Syndrome (ARDS). We discovered two phases of alterations in albumin levels during the course of Covid-19 critical illness, but not for the sepsis-induced ARDS. Our findings suggest the metabolic effects of COVID-19 are pathogen-specific and albumin recovery may signal the cessation of a deleterious immune response in this disease.

Respiratory failure and acute kidney injury (AKI) are associated with high mortality in SARS-CoV-2-associated Coronavirus disease 2019 (COVID-19). These manifestations are linked to a hypercoaguable, pro-inflammatory state with persistent, systemic complement activation. Three critical COVID-19 patients recalcitrant to multiple interventions had skin biopsies documenting deposition of the terminal complement component C5b-9, the lectin complement pathway enzyme MASP2, and C4d in microvascular endothelium. Administration of anti-C5 monoclonal antibody eculizumab led to a marked decline in D-dimers and neutrophil counts in all three cases, and normalization of liver functions and creatinine in two. One patient with severe heart failure and AKI had a complete remission. The other two individuals had partial remissions, one with resolution of his AKI but ultimately succumbing to respiratory failure, and another with a significant decline in FiO2 requirements, but persistent renal failure. In conclusion, anti-complement therapy may be beneficial in at least some patients with critical COVID-19., Highlights • SARS-CoV-2 infection in COVID-19 is associated with sustained complement activation. • Severe COVID-19 involves a pro-inflammatory/hypercoaguable state linked to complement. • Complement deposition in skin of 3 COVID-19 cases recalcitrant to therapy is shown. • Anti-C5 therapy with eculizumab led to 1 complete and 2 partial clinical remissions. • Our data may inform guidelines for earlier intervention with anti-C agents in COVID-19.

The development of chronic lung disease occurs as a consequence of multiple cellular events that involve an initial insult which often leads to the development of chronic inflammation, and the dysregulation of cellular proliferation and cell death mechanisms. Multiple cell types in the lung are key to the respiratory and protective/barrier functions necessary to manage the chronic exposures to environmental, mechanical, and oxidative stressors. Autophagy is essential to lung development and homeostasis, as well as the prevention and development of disease. The cellular process involves the collection and removal of unwanted organelles and proteins through lysosomal degradation. In recent years, investigations have addressed the roles of autophagy and selective autophagy in numerous chronic lung diseases. Here, we highlight recent advances on the role of autophagy in the pathogenesis of asthma, chronic obstructive pulmonary disease and emphysema, pulmonary arterial hypertension, and idiopathic pulmonary fibrosis.

Rationale: Although the transplantation of induced pluripotent stem cell (iPSC)–derived cells harbors enormous potential for the treatment of pulmonary diseases, in vivo data demonstrating clear therapeutic benefits of human iPSC–derived cells in lung disease models are missing. Objectives: We have tested the therapeutic potential of iPSC-derived macrophages in a humanized disease model of hereditary pulmonary alveolar proteinosis (PAP). Hereditary PAP is caused by a genetic defect of the GM-CSF (granulocyte–macrophage colony–stimulating factor) receptor, which leads to disturbed macrophage differentiation and protein/surfactant degradation in the lungs, subsequently resulting in severe respiratory insufficiency. Methods: Macrophages derived from human iPSCs underwent intrapulmonary transplantation into humanized PAP mice, and engraftment, in vivo differentiation, and therapeutic efficacy of the transplanted cells were analyzed. Measurements and Main Results: On intratracheal application, iPSC-derived macrophages engrafted in the lungs of humanized PAP mice. After 2 months, transplanted cells displayed the typical morphology, surface markers, functionality, and transcription profile of primary human alveolar macrophages. Alveolar proteinosis was significantly reduced as demonstrated by diminished protein content and surfactant protein D levels, decreased turbidity of the BAL fluid, and reduced surfactant deposition in the lungs of transplanted mice. Conclusions: We here demonstrate for the first time that pulmonary transplantation of human iPSC–derived macrophages leads to pulmonary engraftment, their in situ differentiation to an alveolar macrophage phenotype, and a reduction of alveolar proteinosis in a humanized PAP model. To our knowledge, this finding presents the first proof-of-concept for the therapeutic potential of human iPSC-derived cells in a pulmonary disease and may have profound implications beyond the rare disease of PAP.

Persistent inflammation within the respiratory tract underlies the pathogenesis of numerous chronic pulmonary diseases including chronic obstructive pulmonary disease, asthma and pulmonary fibrosis. Chronic inflammation in the lung may arise from a combination of genetic susceptibility and environmental influences, including exposure to microbes, particles from the atmosphere, irritants, pollutants, allergens, and toxic molecules. To this end, an immediate, strong, and highly regulated inflammatory defense mechanism is needed for the successful maintenance of homeostasis within the respiratory system. Macroautophagy/autophagy plays an essential role in the inflammatory response of the lung to infection and stress. At baseline, autophagy may be critical for inhibiting spontaneous pulmonary inflammation and fundamental for the response of pulmonary leukocytes to infection; however, when not regulated, persistent or inefficient autophagy may be detrimental to lung epithelial cells, promoting lung injury. This perspective will discuss the role of autophagy in driving and regulating inflammatory responses of the lung in chronic lung diseases with a focus on potential avenues for therapeutic targeting. Abbreviations AR allergic rhinitis AM alveolar macrophage ATG autophagy-related CF cystic fibrosis CFTR cystic fibrosis transmembrane conductance regulator COPD chronic obstructive pulmonary disease CS cigarette smoke CSE cigarette smoke extract DC dendritic cell IH intermittent hypoxia IPF idiopathic pulmonary fibrosis ILD interstitial lung disease MAP1LC3B microtubule associated protein 1 light chain 3 beta MTB Mycobacterium tuberculosis MTOR mechanistic target of rapamycin kinase NET neutrophil extracellular traps OSA obstructive sleep apnea PAH pulmonary arterial hypertension PH pulmonary hypertension ROS reactive oxygen species TGFB1 transforming growth factor beta 1 TNF tumor necrosis factor.

As antimicrobial resistance increases, understanding the current epidemiology of bloodstream infections (BSIs) in hematopoietic stem cell transplant (HSCT) recipients is essential to guide empirical antimicrobial therapy. We therefore reviewed microbial etiologies, timing and outcomes of BSIs in patients who were transplanted from September 2007 to December 2011. Vancomycin-resistant enterococci (VRE) were the most common pathogens in allogeneic HSCT recipients and the fourth most common after autologous transplant. VRE did not cause any of 101 BSIs in neutropenic patients who were not receiving antibacterials, but caused 32 (55%) of 58 BSIs in neutropenic patients receiving a broad-spectrum β-lactam agent (p < 0.001). Rates of septic shock and 7-day mortality were 5% and 0% for streptococcal bacteremia, 12% and 18% for VRE bacteremia, and 20% and 14% for Gram-negative bacteremia. In conclusion, VRE bacteremia was the most common BSI in allogeneic HSCT recipients, occurred primarily in neutropenic patients receiving broad-spectrum β-lactams and was associated with poor outcomes.