Endothelial ENaC-α Restrains Oxidative Stress in Lung Capillaries in Murine Pneumococcal Pneumonia-associated Acute Lung Injury.

Infection of lung endothelial cells with pneumococci activates the superoxide-generating enzyme NADPH oxidase 2 (NOX2), involving the pneumococcal virulence factor pneumolysin (PLY). Excessive NOX2 activity disturbs capillary barriers, but its global inhibition can impair bactericidal phagocyte activity during pneumococcal pneumonia. Depletion of the α subunit of the epithelial sodium channel (ENaC) in pulmonary endothelial cells increases expression and PMA-induced activity of NOX2. Direct ENaC activation by TIP peptide improves capillary barrier function -measured by electrical cell substrate impedance sensing in endothelial monolayers and by Evans Blue Dye incorporation in mouse lungs- following infection with pneumococci. PLY-induced hyperpermeability in HL-MVEC monolayers is abrogated by both NOX2 inhibitor gp91dstat and TIP peptide. Endothelial NOX2 expression is assessed by increased surface membrane presence of phosphorylated p47phox subunit (Western blotting) in vitro and by co-localization of CD31 and gp91phox in mouse lung slices using DuoLink, whereas NOX2-generated superoxide is measured by chemiluminescence. TIP peptide blunts PMA-induced NOX2 activity in cells expressing ENaC-α, but not in neutrophils, which lack ENaC. Conditional endothelial ENaC-α KO (enENaC-α KO) mice develop increased capillary leak upon i.t. instillation with PLY or pneumococci, compared to wild type (wt) animals. TIP peptide diminishes capillary leak in Sp-infected wt mice, without significantly increasing lung bacterial load. Lung slices from Sp-infected enENaC-α KO mice have a significantly increased endothelial NOX2 expression, as compared to infected CRE mice. In conclusion, endothelial ENaC may represent a novel therapeutic target to reduce NOX2-mediated oxidative stress and capillary leak in ARDS, without impairing host defense.

Nebulized caffeine alleviates airway hyperresponsiveness in a murine asthma model.

The clinical definition of "difficult asthma" has expanded recently to include an ever-growing subset of patients with symptoms that cannot be controlled by conventional means, forcing the medical community to develop innovative therapeutics. Beneficial effects of coffee for subjects with asthma, primarily the effect of methylxanthine components, have long been described. Methylxanthines, including theophylline and caffeine, inhibit phosphodiesterases and downstream cAMP signaling to prevent mast cell degranulation while promoting immunomodulation (Peleman RA, Kips JC, Pauwels RA. Clin Exp Allergy 28: 53-56, 1998; Deshpande DA, Wang WCH, McIlmoyle EL, Robinett KS, Schillinger RM, An SS, Sham JSK, Liggett SB. Nat Med 16: 1299-1304, 2010). Caffeine is also a bitter taste receptor agonist, binding to taste-sensing type 2 receptors (TAS2R) before releasing calcium to hyperpolarize airway smooth muscle membranes, inducing bronchodilation (Workman AD, Palmer JN, Adappa ND, Cohen NA. Curr Allergy Asthma Rep 15: 72, 2015; Devillier P, Naline E, Grassin-Delyle S. Pharmacol Ther 155: 11-21, 2015). Theophylline is conventionally used to treat asthma, whereas, according to the literature, the dosage required for orally administered caffeine has yielded modest improvement (Alfaro TM, Monteiro RA, Cunha RA, Cordeiro CR. Clin Respir J 12: 1283-1294, 2018). We sought to determine whether aerosolization of ultrafine caffeine particles (2.5-4 µm) directly to the lungs of susceptible A/J mice challenged with methacholine would improve pulmonary function via forced oscillation technique. In addition, we assessed whether nebulization of caffeine leads to changes in lung pathophysiology and bronchoalveolar lavage cell profiles. We found that mice that received aerosolized caffeine had statistically significant decreases in maximum airway resistance [6.3 vs. 3.9 cmH2O·s/mL at 62.5 mg/mL caffeine; confidence interval (CI) = -4.3, -0.4; P = 0.02] and significant delays in the time required to reach maximum resistance compared with that of controls (64.7 vs. 172.1 sec at 62.5 mg/mL caffeine, CI = 96.0, 118.9; P < 0.0001). Nebulized caffeine yielded a consistent effect on airway hyperresponsiveness at a range of doses without evidence of significant pathology relative to vehicle control.NEW & NOTEWORTHY For decades, coffee has been shown to improve symptoms in patients with asthma. One component, theophylline, is conventionally used to treat asthma, whereas the dosage required for orally administered caffeine has yielded modest improvement. We sought to determine whether aerosolization of caffeine directly to the lungs of susceptible A/J mice challenged with methacholine would alter pulmonary function via forced oscillation technique. We found nebulized caffeine yielded a consistent improvement on murine AHR.

Clinical Trial of Losartan for Pulmonary Emphysema: Pulmonary Trials Cooperative Losartan Effects on Emphysema Progression Clinical Trial.

Rationale: There are no pharmacologic agents that modify emphysema progression in patients with chronic obstructive pulmonary disease (COPD). Objectives: To evaluate the efficacy of losartan, an angiotensin receptor blocker, to reduce emphysema progression. Methods: The trial was a multicenter, randomized, placebo-controlled trial conducted between May 2017 and January 2021. Eligible participants were aged ⩾40 years, had moderate to severe airflow obstruction, ⩾10 pack-years of smoking, mild-moderate emphysema on high-resolution computed tomography, and no medical indication for or intolerance of angiotensin receptor blockers. Treatment with losartan 100 mg daily or matching placebo (1:1) was randomly assigned. The primary outcome was emphysema progression on high-resolution computed tomography over 48 weeks. Secondary outcomes included the St George's Respiratory Questionnaire, the modified Medical Research Council dyspnea scale, the COPD Assessment Test, and the Physical Function-Short Form 20a. Measurements and Main Results: A total of 220 participants were enrolled; 58% were men, 19% were African American, and 24% were current smokers. The medians (interquartile ranges) for age were 65 (61-73) years and 48 (36-59) for percent predicted FEV1 after bronchodilator use. The mean (95% confidence interval) percentage emphysema progression was 1.35% (0.67-2.03) in the losartan group versus 0.66% (0.09-1.23) in the placebo group (P = NS). Conclusions: Losartan did not prevent emphysema progression in people with COPD with mild-moderate emphysema. Clinical trial registered with www.clinicaltrials.gov (NCT02696564).

Treatment of tobacco dependence: current state of the art.

PURPOSE OF REVIEW: The Centers for Medicare and Medicaid Services' requirement to integrate tobacco treatment with lung cancer screening (LCS) has served as a catalyst for motivating pulmonary medicine clinicians to improve upon their ability to effectively treat tobacco dependence. To do so, clinicians need to be well versed in the behavioral and pharmacologic tools that promote smoking cessation. RECENT FINDINGS: The current review outlines current strategies for treating tobacco dependence, focusing on the important interplay between counseling and pharmacotherapy. Studies that have been found to be particularly effective in patients with smoking-related lung disease and in the LCS setting are reviewed. New therapies that are in the pipeline, as well as novel strategies aimed at improving both adoption and effectiveness of existing therapies, are discussed. SUMMARY: Treating tobacco dependence improves mortality and quality of life far more than the limited therapies available to treat smoking-related lung disease. Novel strategies to making tobacco treatment services more widely available, particularly to vulnerable patient populations, are needed to further decrease smoking-related morbidity and mortality. The Affordable Care Act's greater focus on prevention represents a moment of opportunity for healthcare providers and systems to engage in these efforts.

Hepatocyte growth factor, a determinant of airspace homeostasis in the murine lung.

The alveolar compartment, the fundamental gas exchange unit in the lung, is critical for tissue oxygenation and viability. We explored hepatocyte growth factor (HGF), a pleiotrophic cytokine that promotes epithelial proliferation, morphogenesis, migration, and resistance to apoptosis, as a candidate mediator of alveolar formation and regeneration. Mice deficient in the expression of the HGF receptor Met in lung epithelial cells demonstrated impaired airspace formation marked by a reduction in alveolar epithelial cell abundance and survival, truncation of the pulmonary vascular bed, and enhanced oxidative stress. Administration of recombinant HGF to tight-skin mice, an established genetic emphysema model, attenuated airspace enlargement and reduced oxidative stress. Repair in the TSK/+ mouse was punctuated by enhanced akt and stat3 activation. HGF treatment of an alveolar epithelial cell line not only induced proliferation and scattering of the cells but also conferred protection against staurosporine-induced apoptosis, properties critical for alveolar septation. HGF promoted cell survival was attenuated by akt inhibition. Primary alveolar epithelial cells treated with HGF showed improved survival and enhanced antioxidant production. In conclusion, using both loss-of-function and gain-of-function maneuvers, we show that HGF signaling is necessary for alveolar homeostasis in the developing lung and that augmentation of HGF signaling can improve airspace morphology in murine emphysema. Our studies converge on prosurvival signaling and antioxidant protection as critical pathways in HGF-mediated airspace maintenance or repair. These findings support the exploration of HGF signaling enhancement for diseases of the airspace.

Genome-Wide Association Study Identification of Novel Loci Associated with Airway Responsiveness in Chronic Obstructive Pulmonary Disease.

Increased airway responsiveness is linked to lung function decline and mortality in subjects with chronic obstructive pulmonary disease (COPD); however, the genetic contribution to airway responsiveness remains largely unknown. A genome-wide association study (GWAS) was performed using the Illumina (San Diego, CA) Human660W-Quad BeadChip on European Americans with COPD from the Lung Health Study. Linear regression models with correlated meta-analyses, including data from baseline (n = 2,814) and Year 5 (n = 2,657), were used to test for common genetic variants associated with airway responsiveness. Genotypic imputation was performed using reference 1000 Genomes Project data. Expression quantitative trait loci (eQTL) analyses in lung tissues were assessed for the top 10 markers identified, and immunohistochemistry assays assessed protein staining for SGCD and MYH15. Four genes were identified within the top 10 associations with airway responsiveness. Markers on chromosome 9p21.2 flanked by LINGO2 met a predetermined threshold of genome-wide significance (P < 9.57 × 10(-8)). Markers on chromosomes 3q13.1 (flanked by MYH15), 5q33 (SGCD), and 6q21 (PDSS2) yielded suggestive evidence of association (9.57 × 10(-8) < P ≤ 4.6 × 10(-6)). Gene expression studies in lung tissue showed single nucleotide polymorphisms on chromosomes 5 and 3 to act as eQTL for SGCD (P = 2.57 × 10(-9)) and MYH15 (P = 1.62 × 10(-6)), respectively. Immunohistochemistry confirmed localization of SGCD protein to airway smooth muscle and vessels and MYH15 to airway epithelium, vascular endothelium, and inflammatory cells. We identified novel loci associated with airway responsiveness in a GWAS among smokers with COPD. Risk alleles on chromosomes 5 and 3 acted as eQTLs for SGCD and MYH15 messenger RNA, and these proteins were expressed in lung cells relevant to the development of airway responsiveness.

Superoxide dismutase 3 dysregulation in a murine model of neonatal lung injury.

Bronchopulmonary dysplasia (BPD), a common chronic respiratory disease that occurs after premature birth, is believed to be secondary to oxidative damage from hyperoxia and inflammation, which leads to impaired alveolar formation and chronic lung dysfunction. We hypothesized that extracellular superoxide dismutase (SOD)3, an antioxidant uniquely targeted to the extracellular matrix (ECM) and alveolar fluid, might have a different response (down-regulation) to hyperoxic injury and recovery in room air (RA), thereby contributing to the persistent airspace injury and inflammation. We used a murine BPD model using postnatal hyperoxia (O2) (4 or 5 d) followed by short-term recovery (14 d) in RA, which mimics the durable effects after injury during alveolar development. This was associated with significantly increased mRNA expression for antioxidant genes mediated by nuclear factor erythroid 2-related factor (Nrf2) in the O2 (n = 4) versus RA group (n = 5). SOD3, an Nrf2-independent antioxidant, was significantly reduced in the O2-exposed mice compared with RA. Immunohistochemistry revealed decreased and disrupted SOD3 deposition in the alveolar ECM of O2-exposed mice. Furthermore, this distinct hyperoxic antioxidant and injury profile was reproducible in murine lung epithelial 12 cells exposed to O2. Overexpression of SOD3 rescued the injury measures in the O2-exposed cells. We establish that reduced SOD3 expression correlates with alveolar injury measures in the recovered neonatal hyperoxic lung, and SOD3 overexpression attenuates hyperoxic injury in an alveolar epithelial cell line. Such findings suggest a candidate mechanism for the pathogenesis of BPD that may lead to targeted interventions.

A syndrome of altered cardiovascular, craniofacial, neurocognitive and skeletal development caused by mutations in TGFBR1 or TGFBR2.

We report heterozygous mutations in the genes encoding either type I or type II transforming growth factor beta receptor in ten families with a newly described human phenotype that includes widespread perturbations in cardiovascular, craniofacial, neurocognitive and skeletal development. Despite evidence that receptors derived from selected mutated alleles cannot support TGFbeta signal propagation, cells derived from individuals heterozygous with respect to these mutations did not show altered kinetics of the acute phase response to administered ligand. Furthermore, tissues derived from affected individuals showed increased expression of both collagen and connective tissue growth factor, as well as nuclear enrichment of phosphorylated Smad2, indicative of increased TGFbeta signaling. These data definitively implicate perturbation of TGFbeta signaling in many common human phenotypes, including craniosynostosis, cleft palate, arterial aneurysms, congenital heart disease and mental retardation, and suggest that comprehensive mechanistic insight will require consideration of both primary and compensatory events.

Cell type-specific expression of angiotensin receptors in the human lung with implications for health, aging, and chronic disease.

The renin-angiotensin system is a highly characterized integrative pathway in mammalian homeostasis whose clinical spectrum has been expanded to lung disorders such as chronic obstructive pulmonary disease (COPD)-emphysema, idiopathic pulmonary fibrosis (IPF), and COVID pathogenesis. Despite this widespread interest, specific localization of this receptor family in the mammalian lung is limited, partially due to the imprecision of available antibody reagents. In this study, we establish the expression pattern of the two predominant angiotensin receptors in the human lung, AGTR1 and AGTR2, using complementary and comprehensive bulk and single-cell RNA-sequence datasets that are publicly available. We show these two receptors have distinct localization patterns and developmental trajectories in the human lung, pericytes for AGTR1 and a subtype of alveolar epithelial type 2 cells for AGTR2. In the context of disease, we further pinpoint AGTR2 localization to the COPD-associated subpopulation of alveolar epithelial type 2 (AT2B) and AGTR1 localization to fibroblasts, where their expression is upregulated in individuals with COPD, but not in individuals with IPF. Finally, we examine the genetic variation of the angiotensin receptors, finding AGTR2 associated with lung phenotype (i.e., cystic fibrosis) via rs1403543. Together, our findings provide a critical foundation for delineating this pathway's role in lung homeostasis and constructing rational approaches for targeting specific lung disorders.

Genome-wide study identifies two loci associated with lung function decline in mild to moderate COPD.

Accelerated lung function decline is a key COPD phenotype; however, its genetic control remains largely unknown. We performed a genome-wide association study using the Illumina Human660W-Quad v.1_A BeadChip. Generalized estimation equations were used to assess genetic contributions to lung function decline over a 5-year period in 4,048 European American Lung Health Study participants with largely mild COPD. Genotype imputation was performed using reference HapMap II data. To validate regions meeting genome-wide significance, replication of top SNPs was attempted in independent cohorts. Three genes (TMEM26, ANK3 and FOXA1) within the regions of interest were selected for tissue expression studies using immunohistochemistry. Two intergenic SNPs (rs10761570, rs7911302) on chromosome 10 and one SNP on chromosome 14 (rs177852) met genome-wide significance after Bonferroni. Further support for the chromosome 10 region was obtained by imputation, the most significantly associated imputed SNPs (rs10761571, rs7896712) being flanked by observed markers rs10761570 and rs7911302. Results were not replicated in four general population cohorts or a smaller cohort of subjects with moderate to severe COPD; however, we show novel expression of genes near regions of significantly associated SNPS, including TMEM26 and FOXA1 in airway epithelium and lung parenchyma, and ANK3 in alveolar macrophages. Levels of expression were associated with lung function and COPD status. We identified two novel regions associated with lung function decline in mild COPD. Genes within these regions were expressed in relevant lung cells and their expression related to airflow limitation suggesting they may represent novel candidate genes for COPD susceptibility.

Dysregulation of TGF-beta activation contributes to pathogenesis in Marfan syndrome.

Marfan syndrome is an autosomal dominant disorder of connective tissue caused by mutations in fibrillin-1 (encoded by FBN1 in humans and Fbn1 in mice), a matrix component of extracellular microfibrils. A distinct subgroup of individuals with Marfan syndrome have distal airspace enlargement, historically described as emphysema, which frequently results in spontaneous lung rupture (pneumothorax; refs. 1-3). To investigate the pathogenesis of genetically imposed emphysema, we analyzed the lung phenotype of mice deficient in fibrillin-1, an accepted model of Marfan syndrome. Lung abnormalities are evident in the immediate postnatal period and manifest as a developmental impairment of distal alveolar septation. Aged mice deficient in fibrillin-1 develop destructive emphysema consistent with the view that early developmental perturbations can predispose to late-onset, seemingly acquired phenotypes. We show that mice deficient in fibrillin-1 have marked dysregulation of transforming growth factor-beta (TGF-beta) activation and signaling, resulting in apoptosis in the developing lung. Perinatal antagonism of TGF-beta attenuates apoptosis and rescues alveolar septation in vivo. These data indicate that matrix sequestration of cytokines is crucial to their regulated activation and signaling and that perturbation of this function can contribute to the pathogenesis of disease.

The E-cigarette or Vaping Product Use-Associated Lung Injury Epidemic: Pathogenesis, Management, and Future Directions: An Official American Thoracic Society Workshop Report.

E-cigarette or vaping product use-associated lung injury (EVALI) is a severe pulmonary illness associated with the use of e-cigarettes or vaping products that was officially identified and named in 2019. This American Thoracic Society workshop was convened in 2021 to identify and prioritize research and regulatory needs to adequately respond to the EVALI outbreak and to prevent similar instances of disease associated with e-cigarette or vaping product use. An interdisciplinary group of 26 experts in adult and pediatric clinical care, public health, regulatory oversight, and toxicology were convened for the workshop. Four major topics were examined: 1) the public health and regulatory response to EVALI; 2) EVALI clinical care; 3) mechanisms contributing to EVALI; and 4) needed actions to address the health effects of EVALI. Oral presentations and group discussion were the primary modes used to identify top priorities for addressing EVALI. Initiatives including a national EVALI case registry and biorepository, integrated electronic medical record coding system, U.S. Food and Drug Administration regulation and enforcement of nicotine e-cigarette standards, regulatory authority over nontobacco-derived e-cigarettes, training in evaluating exogenous exposures, prospective clinical studies, standardized clinical follow-up assessments, ability to more readily study effects of cannabinoid e-cigarettes, and research to identify biomarkers of exposure and disease were identified as critical needs. These initiatives will require substantial federal investment as well as changes to regulatory policy. Overall, the workshop identified the need to address the root causes of EVALI to prevent future outbreaks. An integrated approach from multiple perspectives is required, including public health; clinical, basic, and translational research; regulators; and users of e-cigarettes. Improving the public health response to reduce the risk of another substantial disease-inducing event depends on coordinated actions to better understand the inhalational toxicity of these products, informing the public of the risks, and developing and enforcing regulatory standards for all e-cigarettes.

Integrated bioinformatics analysis identifies established and novel TGFß1-regulated genes modulated by anti-fibrotic drugs.

Fibrosis is a leading cause of morbidity and mortality worldwide. Although fibrosis may involve different organ systems, transforming growth factor-ß (TGFß) has been established as a master regulator of fibrosis across organs. Pirfenidone and Nintedanib are the only currently-approved drugs to treat fibrosis, specifically idiopathic pulmonary fibrosis, but their mechanisms of action remain poorly understood. To identify novel drug targets and uncover potential mechanisms by which these drugs attenuate fibrosis, we performed an integrative 'omics analysis of transcriptomic and proteomic responses to TGFß1-stimulated lung fibroblasts. Significant findings were annotated as associated with pirfenidone and nintedanib treatment in silico via Coremine. Integrative 'omics identified a co-expressed transcriptomic and proteomic module significantly correlated with TGFß1 treatment that was enriched (FDR-p = 0.04) with genes associated with pirfenidone and nintedanib treatment. While a subset of genes in this module have been implicated in fibrogenesis, several novel TGFß1 signaling targets were identified. Specifically, four genes (BASP1, HSD17B6, CDH11, and TNS1) have been associated with pirfenidone, while five genes (CLINT1, CADM1, MTDH, SYDE1, and MCTS1) have been associated with nintedanib, and MYDGF has been implicated with treatment using both drugs. Using the Clue Drug Repurposing Hub, succinic acid was highlighted as a metabolite regulated by the protein encoded by HSD17B6. This study provides new insights into the anti-fibrotic actions of pirfenidone and nintedanib and identifies novel targets for future mechanistic studies.

Association of sleep apnoea risk and aortic enlargement in Marfan syndrome.

BACKGROUND: Marfan syndrome (MFS) is a connective tissue disorder characterised by complex aortic pathology and a high prevalence of obstructive sleep apnoea (OSA). OSA produces intrathoracic transmural stresses that may accelerate aortic injury. The current study was designed to examine the associations between OSA risk and markers of aortic enlargement in MFS. METHOD: Consecutive patients with MFS were recruited at Johns Hopkins if they completed a STOP-BANG survey. Composite survey scores were categorised into those with low OSA risk (STOP-BANG <3) and high OSA risk (STOP-BANG ≥3). Participants' aortic data were collated to ascertain aortic root diameter, dilatation and prior aortic root replacement. Regression analyses were used to examine associations between OSA risk strata and these aortic parameters. RESULTS: Of the 89 participants studied, 28% had a high OSA risk and 32% had aortic grafts. Persons with high OSA risk had greater aortic root diameter (mm) (ß=4.13, SE=1.81, p=0.027) and aortic root dilatation (ß=2.80, SE=1.34, p=0.046) compared with those with low OSA risk . In addition, the odds of prior aortic root replacement was three times greater in those with high OSA risk compared with those with low OSA risk. CONCLUSION: In MFS, high OSA risk is associated with aortic enlargement and a threefold increased risk of having had prior aortic root replacement. These findings invite further exploration of the relationship between OSA and aortic disease in MFS, and studies to clarify whether targeted interventions for OSA might mitigate aortic disease progression in MFS. REGISTRATION NUMBER: IRB00157483.

Complex integration of matrix, oxidative stress, and apoptosis in genetic emphysema.

Alveolar enlargement, which is characteristic of bronchopulmonary dysplasia, congenital matrix disorders, and cigarette smoke-induced emphysema, is thought to result from enhanced inflammation and ensuing excessive matrix proteolysis. Although there is recent evidence that cell death and oxidative stress punctuate these diseases, the mechanistic link between abnormal lung extracellular matrix and alveolar enlargement is lacking. We hypothesized that the tight-skin (TSK) mouse, which harbors a spontaneous internal duplication in the microfibrillar glycoprotein fibrillin-1, might show whether matrix alterations are sufficient to promote oxidative stress and cell death, injury cascades central to the development of clinical emphysema. We observed no evidence of increased metalloprotease activation by histochemical and zymographic methods. We did find initial oxidative stress followed by increased apoptosis in the postnatal TSK lung. Both blunted antioxidant production and reduced extracellular superoxide dismutase activity were evident in the neonatal lung. High-dose antioxidant treatment with N-acetylcysteine improved airspace caliber and attenuated oxidative stress and apoptosis in neonatal and adult TSK mice. These data establish that an abnormal extracellular matrix without overt elastolysis is sufficient to confer susceptibility to postnatal normoxia, reminiscent of bronchopulmonary dysplasia. The resultant oxidative stress and apoptosis culminate in profound airspace enlargement. The TSK lung exemplifies the critical interplay between extracellular matrix, oxidative stress, and cell-death cascades that may contribute to genetic and acquired airspace enlargement.

Inclusion in the Pulmonary, Critical Care, and Sleep Medicine Physician-Scientist Workforce. Building with Intention.

Physician-scientists comprise an exceedingly small fraction of the physician workforce. As the fields of pulmonary, critical care, and sleep medicine continue to invest in the development of the physician-scientist workforce, recruitment and retention strategies need to consider the temporal trend in the decline in numbers of trainees pursuing basic research, the challenges of trainees from underrepresented groups in medicine, and opportunities for career and scientific advancement of women physician-scientists. In this perspective article, we examine the headwinds in the training and education of physician-scientists and highlight potential solutions to reverse these trends.

IL10 deficiency promotes alveolar enlargement and lymphoid dysmorphogenesis in the aged murine lung.

The connection between aging-related immune dysfunction and the lung manifestations of aging is poorly understood. A detailed characterization of the aging IL10-deficient murine lung, a model of accelerated aging and frailty, reconciles features of both immunosenescence and lung aging in a coherent model. Airspace enlargement developed in the middle-aged (12 months old) and aged (20-22 months old) IL10-deficient lung punctuated by an expansion of macrophages and alveolar cell apoptosis. Compared to wild-type (WT) controls, the IL10-deficient lungs from young (4-month-old) mice showed increased oxidative stress which was enhanced in both genotypes by aging. Active caspase 3 staining was increased in the alveolar epithelial cells of aged WT and mutant lungs but was greater in the IL10-deficient milieu. Lung macrophages were increased in the aged IL10-deficient lungs with exuberant expression of MMP12. IL10 treatment of naïve and M2-polarized bone marrow-derived WT macrophages reduced MMP12 expression. Conditioned media studies demonstrated the secretome of aged mutant macrophages harbors reduced AECII prosurvival factors, specifically keratinocyte growth factor (KGF) and hepatocyte growth factor (HGF), promotes cell death, and reduces survival of primary alveolar epithelial cells. Compared to WT controls, aged IL10-deficient mice have increased parenchymal lymphoid collections comprised of a reduced number of apoptotic cells and B cells. We establish that IL10 is a key modulator of airspace homeostasis and lymphoid morphogenesis in the aging lung enabling macrophage-mediated alveolar epithelial cell survival and B-cell survival within tertiary lymphoid structures.