A role for TMEM63 in the lung.

Surfactants are essential for breathing. Although major progress has been made in the past half century toward an understanding of surfactant secretion mechanisms, the identity of the mechanosensor that couples breathing to surfactant secretion has remained elusive. In this issue of the JCI, Chen, Li, and colleagues provide evidence that the mechanosensor is the transmembrane 63 (TMEM63) ion channel. These findings open new avenues for future research into lung mechanobiology.

The pathogenesis of influenza in intact alveoli: virion endocytosis and its effects on the lung's air-blood barrier.

Lung infection by influenza A virus (IAV) is a major cause of global mortality from lung injury, a disease defined by widespread dysfunction of the lung's air-blood barrier. Endocytosis of IAV virions by the alveolar epithelium - the cells that determine barrier function - is central to barrier loss mechanisms. Here, we address the current understanding of the mechanistic steps that lead to endocytosis in the alveolar epithelium, with an eye to how the unique structure of lung alveoli shapes endocytic mechanisms. We highlight where future studies of alveolar interactions with IAV virions may lead to new therapeutic approaches for IAV-induced lung injury.

Rescue of alveolar wall liquid secretion blocks fatal lung injury due to influenza-staphylococcal coinfection.

Secondary lung infection by inhaled Staphylococcus aureus (SA) is a common and lethal event for individuals infected with influenza A virus (IAV). How IAV disrupts host defense to promote SA infection in lung alveoli, where fatal lung injury occurs, is not known. We addressed this issue using real-time determinations of alveolar responses to IAV in live, intact, perfused lungs. Our findings show that IAV infection blocked defensive alveolar wall liquid (AWL) secretion and induced airspace liquid absorption, thereby reversing normal alveolar liquid dynamics and inhibiting alveolar clearance of inhaled SA. Loss of AWL secretion resulted from inhibition of the cystic fibrosis transmembrane conductance regulator (CFTR) ion channel in the alveolar epithelium, and airspace liquid absorption was caused by stimulation of the alveolar epithelial Na+ channel (ENaC). Loss of AWL secretion promoted alveolar stabilization of inhaled SA, but rescue of AWL secretion protected against alveolar SA stabilization and fatal SA-induced lung injury in IAV-infected mice. These findings reveal a central role for AWL secretion in alveolar defense against inhaled SA and identify AWL inhibition as a critical mechanism of IAV lung pathogenesis. AWL rescue may represent a new therapeutic approach for IAV-SA coinfection.

New Insights into the Alveolar Epithelium as a Driver of Acute Respiratory Distress Syndrome.

The alveolar epithelium serves as a barrier between the body and the external environment. To maintain efficient gas exchange, the alveolar epithelium has evolved to withstand and rapidly respond to an assortment of inhaled, injury-inducing stimuli. However, alveolar damage can lead to loss of alveolar fluid barrier function and exuberant, non-resolving inflammation that manifests clinically as acute respiratory distress syndrome (ARDS). This review discusses recent discoveries related to mechanisms of alveolar homeostasis, injury, repair, and regeneration, with a contemporary emphasis on virus-induced lung injury. In addition, we address new insights into how the alveolar epithelium coordinates injury-induced lung inflammation and review maladaptive lung responses to alveolar damage that drive ARDS and pathologic lung remodeling.

A shift in lung macrophage composition is associated with COVID-19 severity and recovery.

Although it has been more than 2 years since the start of the coronavirus disease 2019 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, therapies to treat COVID-19 and other inflammatory diseases remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and mortality to develop tailored immunotherapy strategies to halt disease progression. We assembled the Mount Sinai COVID-19 Biobank, which was composed of almost 600 hospitalized patients followed longitudinally through the peak of the pandemic in 2020. Moderate disease and survival were associated with a stronger antigen presentation and effector T cell signature. In contrast, severe disease and death were associated with an altered antigen presentation signature, increased numbers of inflammatory immature myeloid cells, and extrafollicular activated B cells that have been previously associated with autoantibody formation. In severely ill patients with COVID-19, lung tissue-resident alveolar macrophages not only were drastically depleted but also had an altered antigen presentation signature, which coincided with an influx of inflammatory monocytes and monocyte-derived macrophages. In addition, we found that the size of the alveolar macrophage pool correlated with patient outcome and that alveolar macrophage numbers and functionality were restored to homeostasis in patients who recovered from COVID-19. These data suggest that local and systemic myeloid cell dysregulation are drivers of COVID-19 severity and modulation of alveolar macrophage numbers and activity in the lung may be a viable therapeutic strategy for the treatment of critical inflammatory lung diseases.

Shift of lung macrophage composition is associated with COVID-19 disease severity and recovery.

Though it has been 2 years since the start of the Coronavirus Disease 19 (COVID-19) pandemic, COVID-19 continues to be a worldwide health crisis. Despite the development of preventive vaccines, very little progress has been made to identify curative therapies to treat COVID-19 and other inflammatory diseases which remain a major unmet need in medicine. Our study sought to identify drivers of disease severity and death to develop tailored immunotherapy strategies to halt disease progression. Here we assembled the Mount Sinai COVID-19 Biobank which was comprised of ~600 hospitalized patients followed longitudinally during the peak of the pandemic. Moderate disease and survival were associated with a stronger antigen (Ag) presentation and effector T cell signature, while severe disease and death were associated with an altered Ag presentation signature, increased numbers of circulating inflammatory, immature myeloid cells, and extrafollicular activated B cells associated with autoantibody formation. Strikingly, we found that in severe COVID-19 patients, lung tissue resident alveolar macrophages (AM) were not only severely depleted, but also had an altered Ag presentation signature, and were replaced by inflammatory monocytes and monocyte-derived macrophages (MoMΦ). Notably, the size of the AM pool correlated with recovery or death, while AM loss and functionality were restored in patients that recovered. These data therefore suggest that local and systemic myeloid cell dysregulation is a driver of COVID-19 severity and that modulation of AM numbers and functionality in the lung may be a viable therapeutic strategy for the treatment of critical lung inflammatory illnesses.

Generation and persistence of human tissue-resident memory T cells in lung transplantation.

Tissue-resident memory T cells (TRM) maintain immunity in diverse sites as determined in mouse models, whereas their establishment and role in human tissues have been difficult to assess. Here, we investigated human lung TRM generation, maintenance, and function in airway samples obtained longitudinally from human leukocyte antigen (HLA)-disparate lung transplant recipients, where donor and recipient T cells could be localized and tracked over time. Donor T cells persist specifically in the lungs (and not blood) of transplant recipients and express high levels of TRM signature markers including CD69, CD103, and CD49a, whereas lung-infiltrating recipient T cells gradually acquire TRM phenotypes over months in vivo. Single-cell transcriptome profiling of airway T cells reveals that donor T cells comprise two TRM-like subsets with varying levels of expression of TRM-associated genes, whereas recipient T cells comprised non-TRM and similar TRM-like subpopulations, suggesting de novo TRM generation. Transplant recipients exhibiting higher frequencies of persisting donor TRM experienced fewer adverse clinical events such as primary graft dysfunction and acute cellular rejection compared with recipients with low donor TRM persistence, suggesting that monitoring TRM dynamics could be clinically informative. Together, our results provide spatial and temporal insights into how human TRM develop, function, persist, and affect tissue integrity within the complexities of lung transplantation.

Regulatory T Cells Promote Macrophage Efferocytosis during Inflammation Resolution.

Regulatory T (Treg) cell responses and apoptotic cell clearance (efferocytosis) represent critical arms of the inflammation resolution response. We sought to determine whether these processes might be linked through Treg-cell-mediated enhancement of efferocytosis. In zymosan-induced peritonitis and lipopolysaccharide-induced lung injury, Treg cells increased early in resolution, and Treg cell depletion decreased efferocytosis. In advanced atherosclerosis, where defective efferocytosis drives disease progression, Treg cell expansion improved efferocytosis. Mechanistic studies revealed the following sequence: (1) Treg cells secreted interleukin-13 (IL-13), which stimulated IL-10 production in macrophages; (2) autocrine-paracrine signaling by IL-10 induced Vav1 in macrophages; and (3) Vav1 activated Rac1 to promote apoptotic cell engulfment. In summary, Treg cells promote macrophage efferocytosis during inflammation resolution via a transcellular signaling pathway that enhances apoptotic cell internalization. These findings suggest an expanded role of Treg cells in inflammation resolution and provide a mechanistic basis for Treg-cell-enhancement strategies for non-resolving inflammatory diseases.

Low-Burden Strategies to Promote Smoking Cessation Treatment Among Patients With Serious Mental Illness.

Patients with serious mental illness have high smoking prevalence and early mortality. Inadequate implementation of evidence-based smoking cessation treatment in community mental health centers (CMHCs) contributes to this disparity. This column describes a study of the effects of quality improvement strategies on treatment and cessation outcomes among patients with serious mental illness at four CMHCs. Two low-burden strategies, decision support and academic detailing with data-driven feedback, were implemented in the CMHCs' clinics from 2014 to 2016. Pre- and postimplementation data from pharmacy and medical records were analyzed. The percentage of patients receiving cessation medication increased from 5% to 18% (p≤.001), and smoking prevalence decreased from 57% to 54% (p≤.001). This quality improvement approach holds great potential for increasing the level of smoking cessation care for patients treated in CMHC settings. Decision support and academic detailing with feedback may be effective strategies to promote best practices.

Disruption of staphylococcal aggregation protects against lethal lung injury.

Infection by Staphylococcus aureus strain USA300 causes tissue injury, multiorgan failure, and high mortality. However, the mechanisms by which the bacteria adhere to, then stabilize on, mucosal surfaces before causing injury remain unclear. We addressed these issues through the first real-time determinations of USA300-alveolar interactions in live lungs. We found that within minutes, inhaled USA300 established stable, self-associated microaggregates in niches at curved, but not at flat, regions of the alveolar wall. The microaggregates released α-hemolysin toxin, causing localized alveolar injury, as indicated by epithelial dye loss, mitochondrial depolarization, and cytosolic Ca2+ increase. Spread of cytosolic Ca2+ through intercellular gap junctions to adjoining, uninfected alveoli caused pulmonary edema. Systemic pretreatment with vancomycin, a USA300-cidal antibiotic, failed to protect mice infected with inhaled WT USA300. However, vancomycin pretreatment markedly abrogated mortality in mice infected with mutant USA300 that lacked the aggregation-promoting factor PhnD. We interpret USA300-induced mortality as having resulted from rapid bacterial aggregation in alveolar niches. These findings indicate, for the first time to our knowledge, that alveolar microanatomy is critical in promoting the aggregation and, hence, in causing USA300-induced alveolar injury. We propose that in addition to antibiotics, strategies for bacterial disaggregation may constitute novel therapy against USA300-induced lung injury.

Geographic disparities in donor lung supply and lung transplant waitlist outcomes: A cohort study.

Despite the Final Rule mandate for equitable organ allocation in the United States, geographic disparities exist in donor lung allocation, with the majority of donor lungs being allocated locally to lower-priority candidates. We conducted a retrospective cohort study of 19 622 lung transplant candidates waitlisted between 2006 and 2015. We used multivariable adjusted competing risk survival models to examine the relationship between local lung availability and waitlist outcomes. The primary outcome was a composite of death and removal from the waitlist for clinical deterioration. Waitlist candidates in the lowest quartile of local lung availability had an 84% increased risk of death or removal compared with candidates in the highest (subdistribution hazard ratio [SHR]: 1.84, 95% confidence interval [CI]: 1.51-2.24, P < .001). The transplantation rate was 57% lower in the lowest quartile compared with the highest (SHR: 0.43, 95% CI: 0.39-0.47). The adjusted death or removal rate decreased by 11% with a 50% increase in local lung availability (SHR: 0.89, 95% CI: 0.85-0.93, P < .001) and the adjusted transplantation rate increased by 19% (SHR: 1.19, 95% CI: 1.17-1.22, P < .001). There are geographically disparate waitlist outcomes in the current lung allocation system. Candidates listed in areas of low local lung availability have worse waitlist outcomes.

Selecting lung transplant candidates: where do current guidelines fall short?

In 2010, 1770 lung transplant procedures were performed in the USA, yet 2469 new candidates were added to the waiting list the same year. The shortage of suitable donor lungs requires that transplant professionals select patients for lung transplantation only if they are likely to sustain a survival benefit from the procedure. However, 20% of lung transplant recipients die within the first year of transplantation, suggesting that we are failing to identify those at high risk for severe early complications. In this perspective, we review the current guidelines for the selection of lung transplant candidates, which are based largely on expert opinion and small case series. We also propose the study of new extrapulmonary factors, such as frailty and sarcopenia, that might help improve the prediction of complications and early death after lung transplantation, leading to an improved candidate selection process.