An atlas of epithelial cell states and plasticity in lung adenocarcinoma.

Understanding the cellular processes that underlie early lung adenocarcinoma (LUAD) development is needed to devise intervention strategies1. Here we studied 246,102 single epithelial cells from 16 early-stage LUADs and 47 matched normal lung samples. Epithelial cells comprised diverse normal and cancer cell states, and diversity among cancer cells was strongly linked to LUAD-specific oncogenic drivers. KRAS mutant cancer cells showed distinct transcriptional features, reduced differentiation and low levels of aneuploidy. Non-malignant areas surrounding human LUAD samples were enriched with alveolar intermediate cells that displayed elevated KRT8 expression (termed KRT8+ alveolar intermediate cells (KACs) here), reduced differentiation, increased plasticity and driver KRAS mutations. Expression profiles of KACs were enriched in lung precancer cells and in LUAD cells and signified poor survival. In mice exposed to tobacco carcinogen, KACs emerged before lung tumours and persisted for months after cessation of carcinogen exposure. Moreover, they acquired Kras mutations and conveyed sensitivity to targeted KRAS inhibition in KAC-enriched organoids derived from alveolar type 2 (AT2) cells. Last, lineage-labelling of AT2 cells or KRT8+ cells following carcinogen exposure showed that KACs are possible intermediates in AT2-to-tumour cell transformation. This study provides new insights into epithelial cell states at the root of LUAD development, and such states could harbour potential targets for prevention or intervention.

The association between body weight indices, behavioral factors, and type 2 diabetes mellitus in Africa: A systematic review and meta-analysis of population-based epidemiological studies.

BACKGROUND AND AIM: Type 2 diabetes mellitus (T2DM) is a significant public health concern in Africa. While the associations between modifiable risk factors and T2DM are likely to be Africa-specific, their overall estimations have not been published. This study aimed to use systematic and meta-analytic methods to examine the strength of associations between modifiable risk factors and T2DM in Africa. METHODS AND RESULTS: A systematic search of literature published between January 2000 to March 2022 was conducted. The review included only population-based studies and data extracted from 57 studies. Of these, unadjusted data from 50 studies were included in meta-analysis. With considerable heterogeneity between studies, random-effect models were calculated to ascertain the odds ratios (OR) and 95% confidence intervals (CI) for the associations between obesity (OB) and overweight (OV), defined by BMI; central obesity (waist circumference (OB-WC), waist-to-hip-ratio (OB-WHR)), alcohol, fruit and vegetable consumption, smoking, physical activity (PA) and T2DM. Moderator effects of age, African regions, and urban/rural location were assessed. Risk factors associated with T2DM include BMI-OB [OR = 3.05, 95% CI: (2.58, 3.61)], BMI-OV [OR = 2.38, 95% CI: (1.51, 3.75)], and BMI-OV/OB [OR = 2.07, 95% CI: (1.82, 2.34)]; OB-WC [OR = 2.58, 95% CI: (2.09, 3.18)] and OB-WHR [OR = 2.22, 95% CI: (1.69, 2.92)]; PA [OR = 1.85, 95% CI: (1.50, 2.30)]. Significant moderator effects were not observed. CONCLUSION: Obesity defined by BMI and central obesity, but not behavioral risk factors were most strongly associated with T2DM in African populations, emphasizing the need for obesity prevention to limit the rise of T2DM. REGISTRATION: The PROSPERO registration number is CRD42016043027.

The molecular and cellular mechanisms associated with the destruction of terminal bronchioles in COPD.

RATIONALE: Peripheral airway obstruction is a key feature of chronic obstructive pulmonary disease (COPD), but the mechanisms of airway loss are unknown. This study aims to identify the molecular and cellular mechanisms associated with peripheral airway obstruction in COPD. METHODS: Ten explanted lung specimens donated by patients with very severe COPD treated by lung transplantation and five unused donor control lungs were sampled using systematic uniform random sampling (SURS), resulting in 240 samples. These samples were further examined by micro-computed tomography (CT), quantitative histology and gene expression profiling. RESULTS: Micro-CT analysis showed that the loss of terminal bronchioles in COPD occurs in regions of microscopic emphysematous destruction with an average airspace size of ≥500 and <1000 µm, which we have termed a "hot spot". Based on microarray gene expression profiling, the hot spot was associated with an 11-gene signature, with upregulation of pro-inflammatory genes and downregulation of inhibitory immune checkpoint genes, indicating immune response activation. Results from both quantitative histology and the bioinformatics computational tool CIBERSORT, which predicts the percentage of immune cells in tissues from transcriptomic data, showed that the hot spot regions were associated with increased infiltration of CD4 and CD8 T-cell and B-cell lymphocytes. INTERPRETATION: The reduction in terminal bronchioles observed in lungs from patients with COPD occurs in a hot spot of microscopic emphysema, where there is upregulation of IFNG signalling, co-stimulatory immune checkpoint genes and genes related to the inflammasome pathway, and increased infiltration of immune cells. These could be potential targets for therapeutic interventions in COPD.

Effect of age and sex on the associations between potential modifiable risk factors and both type 2 diabetes and impaired fasting glycaemia among West African adults.

BACKGROUND: Type 2 diabetes mellitus (T2DM) is becoming one of the leading causes of morbidity and mortality worldwide, including among Africans. Knowledge of the association between traditional risk factors and both diabetes and pre-diabetes, and whether these differ by age and sex, is important for designing targeted interventions. However, little is known about these associations for African populations. METHODS: The study used data from WHO STEPS surveys, comprising 15,520 participants (6,774 men and 8,746 women) aged 25-64 years, from 5 different West African countries, namely Burkina Faso (4,711), Benin (3,816), Mali (1,772), Liberia (2,594), and Ghana (2,662). T-test and chi-square tests were used to compare differences in the prevalence of traditional risk factors for both sexes. Multinomial logistic regression was conducted to ascertain the relative risks (RR) and 95% confidence intervals (CI) for both T2DM and impaired fasting glucose (IFG) relating to each risk factor, including obesity [defined by BMI, waist circumference (WC), waist-to-hip ratio (WHR), and waist-to-height ratio (WHtR)], high blood pressure (HBP), fruit and vegetable consumption, physical inactivity, alcohol consumption, and smoking. Models for each of these traditional risk factors and interactions with age and sex were fitted. RESULTS: Factors associated with T2DM and IFG were age, obesity [defined by BMI, WC, WHtR, and WHR], HBP, smoking, physical inactivity, and fruit and vegetable consumption (p < 0.05). Analysis of interaction effects showed few significant differences in associations between risk factors and T2DM according to age or sex. Significant interaction with age was observed for HBP*age and T2DM [RR; 1.20, 95% CI: (1.01, 1.42)) (p = 0.04)], WHtR*age and T2DM [RR; 1.23, 95% CI: (1.06, 1.44) (p = 0.007)] and WHR*age and IFG [RR: 0.79, 95% CI: (0.67, 0.94) (p = 0.006)]. Some interactions with age and sex were observed for the association of alcohol consumption and both IFG and T2DM, but no clear patterns were observed. CONCLUSION: The study found that with very few exceptions, associations between traditional risk factors examined and both IFG and T2DM did not vary by age or sex among the West African population. Policies and public health intervention strategies for the prevention of T2DM and IFG should target adults of any age or sex in West Africa.

Differential expression of sputum and serum autoantibodies in patients with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is a complex and progressive respiratory disease. Autoimmune processes have been hypothesized to contribute to disease progression; however, the presence of autoantibodies in the serum has been variable. Given that COPD is a lung disease, we sought to investigate whether autoantibodies in sputum supernatant would better define pulmonary autoimmune processes. Matched sputum and serum samples were obtained from the Airways Disease Endotyping for Personalized Therapeutics (ADEPT) study and at the Guangzhou Institute of Respiratory Health (GIRH). Samples were collected from patients with varying severity of COPD, asymptomatic smokers, and healthy control subjects. IgG and IgM autoantibodies were detected in sputum and serum of all subjects in both cohorts using a broad-spectrum autoantigen array. No differences were observed in sputum autoantibodies between COPD and asymptomatic smokers in either cohort. In contrast, 16% of detectable sputum IgG autoantibodies were decreased in subjects with COPD compared to healthy controls in the ADEPT cohort. Compared to asymptomatic smokers, approximately 13% of detectable serum IgG and 40% of detectable serum IgM autoantibodies were differentially expressed in GIRH COPD subjects. Of the differentially expressed specificities, anti-nuclear autoantibodies were predominately decreased. A weak correlation between increased serum IgM anti-tissue autoantibodies and a measure of airspace enlargement was observed. The differential expression of specificities varied between the cohorts. In closing, using a comprehensive autoantibody array, we demonstrate that autoantibodies are present in subjects with COPD, asymptomatic smokers, and healthy controls. Cohorts displayed high levels of heterogeneity, precluding the utilization of autoantibodies for diagnostic purposes.

Associations between obesity indices and both type 2 diabetes and impaired fasting glucose among West African adults: Results from WHO STEPS surveys.

BACKGROUND AND AIM: Various obesity indices such as BMI, waist circumference (WC), waist-hip ratio, (WHR) and waist-to-height ratio (WHtR) are associated with the risk of type 2 Diabetes Mellitus (T2DM). Given few studies examining the strength of the association in this population, we aimed to identify which obesity indices are most strongly associated with T2DM and impaired fasting glucose (IFG) among adults from five West African countries. METHODS AND RESULTS: Data from 15,520 participants from the World Health Organisation (WHO) STEPs surveys in Burkina Faso, Benin, Mali, Liberia, and Ghana were included in analyses. Multinomial logistic regression was used to calculate the relative risk (RR) per standard deviation (SD) of each anthropometric measure, modelled as both continuous variables and as categorical variables based on established cut-points. In the analyses with continuous variables, the unadjusted RRs for T2DM per SD were 1.30 (1.23, 1.37) for body mass index (BMI); 1.56 (1.46, 1.67) for WC; 2.57 (2.15, 3.09) for WHtR and 1.16 (1.03, 1.31) for WHR. WHtR showed the strongest association with T2DM in all adjusted analyses. For models using categorical variables based on established cut-points, obesity defined using waist circumference (OB-WC) and OB-BMI showed the strongest associations with T2DM, and OB-WHR, the weakest association in all adjusted analyses. CONCLUSION: WHtR and WC appear to be the indices most strongly associated with T2DM and IFG respectively. Given its simplicity, WC may be the metric that most usefully conveys risk for T2DM in West African adults.

Pathological Comparisons of Paraseptal and Centrilobular Emphysema in Chronic Obstructive Pulmonary Disease.

Rationale: Although centrilobular emphysema (CLE) and paraseptal emphysema (PSE) are commonly identified on multidetector computed tomography (MDCT), little is known about the pathology associated with PSE compared with that of CLE.Objectives: To assess the pathological differences between PSE and CLE in chronic obstructive pulmonary disease (COPD).Methods: Air-inflated frozen lung specimens (n = 6) obtained from patients with severe COPD treated by lung transplantation were scanned with MDCT. Frozen tissue cores were taken from central (n = 8) and peripheral (n = 8) regions of each lung, scanned with micro-computed tomography (microCT), and processed for histology. The core locations were registered to the MDCT, and a percentage of PSE or CLE was assigned by radiologists to each of the regions. MicroCT scans were used to measure number and structural change of terminal bronchioles. Furthermore, microCT-based volume fractions of CLE and PSE allowed classifying cores into mild emphysema, CLE-dominant, and PSE-dominant.Measurements and Main Results: The percentages of PSE measured on MDCT and microCT were positively associated (P = 0.015). The number of terminal bronchioles per milliliter of lung and cross-sectional lumen area were significantly lower and wall area percentage was significantly higher in CLE-dominant regions compared with mild emphysema and PSE-dominant regions (all P < 0.05), whereas no difference was found between PSE-dominant and mild emphysema samples (all P > 0.5). Immunohistochemistry showed significantly higher infiltration of neutrophils (P = 0.002), but not of macrophages, CD4, CD8, or B cells, in PSE compared with CLE regions.Conclusions: The terminal bronchioles are relatively preserved, whereas neutrophilic inflammation is increased in PSE-dominant regions compared with CLE-dominant regions in patients with COPD.

Exploring health state utility values of parents of children with a serious illness.

PURPOSE: In cost-utility analysis, outcomes are usually measured in terms of quality-adjusted life years, where length of life is adjusted by levels of health-related quality of life (HRQoL) using a single value, known as a health state utility value (HSUV). This study explores the HSUVs of parents of children with a serious illness admitted within three hospital departments (cardiology, oncology and paediatric intensive care) across four time points, compares HSUVs with Australian population norms and examines predictors of parental HSUVs. METHODS: Data were obtained from the Take a Breath study, where parental HSUVs were measured using the Assessment of Quality of Life-8 Dimensions (AQoL-8D). Descriptive statistics and t-tests compared the AQoL-8D scores with population norms, while repeated measures ANOVA was used to compare parental HSUVs of children treated across illness groups over time. Regression analysis was performed to determine predictors of parental HSUVs. RESULTS: Parental HSUVs were not significantly different from the general Australian population norms (p = 0.939), as measured by the AQoL-8D. However, statistically significant differences were observed in the psychosocial super-dimension (p < 0.01) and in all eight AQoL-8D dimensions, except for senses and self-worth. No significant differences were observed across illness groups. Parental HSUVs were associated with psychosocial risk factors of trait anxiety (p < 0.001), depression (p < 0.001) and family beliefs (p = 0.024). CONCLUSION: Having a child with a severe illness has an impact on the psychosocial aspects of parental HRQoL regardless of the type of illness. Psychosocial health factors of trait anxiety, depression and family beliefs were important predictors of parental HSUV.

Pharmacologic targeting of the ATX/LPA axis attenuates bleomycin-induced pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a chronic fibrosing lung disease with a dismal prognosis and a largely unknown etiology. Autotaxin (ATX) is a secreted lysophospholipase D, largely responsible for extracellular production of lysophosphatidic acid (LPA), a bioactive phospholipid. LPA has numerous effects in most cell types, signaling through at least 6 receptors (LPAR) exhibiting wide spread distribution and overlapping specificities. The ATX/LPA axis has been suggested as a therapeutic target in different chronic inflammatory and fibroproliferative disorders, including pulmonary fibrosis. In this report, we examined head-to-head the efficacy of a potent inhibitor of ATX (PF-8380), that has not been tested in pulmonary fibrosis models, and an antagonist of LPAR1 (AM095) in bleomycin (BLM)-induced pulmonary fibrosis. Both compounds abrogated the development of pulmonary fibrosis and prevented the distortion of lung architecture, exhibiting qualitative and quantitative differences in different manifestations of the modeled disease.

Changes in waist circumference independent of weight: Implications for population level monitoring of obesity.

Population monitoring of obesity is most commonly conducted using body mass index (BMI). We test the hypothesis that because of increases in waist circumference (WC) independent of increases in weight, BMI alone detects an increasingly smaller proportion of the population with obesity. METHODS: Australian adults with measured height, weight, and WC were selected from three nationally representative cross-sectional surveys (1989, 1999-2000, 2011-12; n=8313, 5903 & 3904). Participants were defined as having obesity using classifications for an obese BMI (≥30kg·m-2) and substantially-increased-risk WC (≥88cm [women], ≥102cm [men]). Age-standardised prevalence of obesity according to BMI and/or WC, and the proportion of these detected by BMI and by WC were compared across surveys. FINDINGS: Between 1989 and 2011-12, weight and WC increased by 5.4kg and 10.7cm (women), and by 7.0kg and 7.3cm (men). For women and men, 63% and 38% of increases in WC were independent of increases in weight. Over this period, the prevalence of obesity according to BMI and/or WC increased by 25.3 percentage-points for women (18.9% to 44.3%) and 21.1 percentage-points for men (17.1% to 38.2%). The proportion of these detected by BMI decreased for women by 20 percentage-points (77% to 57%) with no change for men. The proportion of these detected by WC increased for women and men by 10 percentage-points (87% to 97%) and 6 percentage-points (85% to 91%) respectively. CONCLUSION: BMI alone is detecting a decreasing proportion of those considered obese by BMI and/or WC. Renewed discussion regarding how we monitor obesity at the population level is required.

Variation in Rapa Nui (Easter Island) land use indicates production and population peaks prior to European contact.

Many researchers believe that prehistoric Rapa Nui society collapsed because of centuries of unchecked population growth within a fragile environment. Recently, the notion of societal collapse has been questioned with the suggestion that extreme societal and demographic change occurred only after European contact in AD 1722. Establishing the veracity of demographic dynamics has been hindered by the lack of empirical evidence and the inability to establish a precise chronological framework. We use chronometric dates from hydrated obsidian artifacts recovered from habitation sites in regional study areas to evaluate regional land-use within Rapa Nui. The analysis suggests region-specific dynamics including precontact land use decline in some near-coastal and upland areas and postcontact increases and subsequent declines in other coastal locations. These temporal land-use patterns correlate with rainfall variation and soil quality, with poorer environmental locations declining earlier. This analysis confirms that the intensity of land use decreased substantially in some areas of the island before European contact.

Intubation Success after Introduction of a Quality Assurance Program Using Video Laryngoscopy.

OBJECTIVE: The deployment of video laryngoscopy devices that include recording capability presents a new and unique opportunity for medical directors to review prehospital patient encounters. We sought to evaluate the effect of introducing a video laryngoscope and video quality assurance program to an air medical program on measures of intubation success including overall success, first-pass success, success within 2 attempts, and the total number of attempts. METHODS: This was a retrospective review of data collected on intubations by nurses and paramedics of the Virginia State Police Med-Flight 1 air medical program. RESULTS: After introduction of the video laryngoscope and quality assurance program, the overall intubation success improved to 100% but did not reach statistical significance (95% confidence interval [CI], -4.40 to 12.57; P = .25). First-pass success improved from 76.19% to 92.86% (CI, 1.14-33.14; P = .02), whereas the average attempts declined from 1.31 to 1.09 per patient encounter (CI, -.41 to -.03; P = .02). Success within 2 attempts was 92.86% before the intervention and 98.21% after (CI, 4.25-17.82; P = .19). CONCLUSION: Video laryngoscopy and a robust means for medical director oversight are important components of a high-performance airway management program and demonstrably improve intubation first-pass success.

Cigarette Smoke Attenuates the Nasal Host Response to Streptococcus pneumoniae and Predisposes to Invasive Pneumococcal Disease in Mice.

Streptococcus pneumoniae is a leading cause of invasive bacterial infections, with nasal colonization an important first step in disease. While cigarette smoking is a strong risk factor for invasive pneumococcal disease, the underlying mechanisms remain unknown. This is partly due to a lack of clinically relevant animal models investigating nasal pneumococcal colonization in the context of cigarette smoke exposure. We present a model of nasal pneumococcal colonization in cigarette smoke-exposed mice and document, for the first time, that cigarette smoke predisposes to invasive pneumococcal infection and mortality in an animal model. Cigarette smoke increased the risk of bacteremia and meningitis without prior lung infection. Mechanistically, deficiency in interleukin 1α (IL-1α) or platelet-activating factor receptor (PAFR), an important host receptor thought to bind and facilitate pneumococcal invasiveness, did not rescue cigarette smoke-exposed mice from invasive pneumococcal disease. Importantly, we observed cigarette smoke to attenuate nasal inflammatory mediator expression, particularly that of neutrophil-recruiting chemokines, normally elicited by pneumococcal colonization. Smoking cessation during nasal pneumococcal colonization rescued nasal neutrophil recruitment and prevented invasive disease in mice. We propose that cigarette smoke predisposes to invasive pneumococcal disease by suppressing inflammatory processes of the upper respiratory tract. Given that smoking prevalence remains high worldwide, these findings are relevant to the continued efforts to reduce the invasive pneumococcal disease burden.

Persistence of circulating endothelial microparticles in COPD despite smoking cessation.

INTRODUCTION: Increasing evidence links COPD pathogenesis with pulmonary capillary apoptosis. We previously demonstrated that plasma levels of circulating microparticles released from endothelial cells (EMPs) due to apoptosis are elevated in smokers with normal spirometry but low diffusion capacity, that is, with early evidence of lung destruction. We hypothesised that pulmonary capillary apoptosis persists with the development of COPD and assessed its reversibility in healthy smokers and COPD smokers following smoking cessation. METHODS: Pulmonary function and high-resolution CT (HRCT) were assessed in 28 non-smokers, 61 healthy smokers and 49 COPD smokers; 17 healthy smokers and 18 COPD smokers quit smoking for 12 months following the baseline visit. Total EMP (CD42b-CD31+), pulmonary capillary EMP (CD42b-CD31+ACE+) and apoptotic EMP (CD42b-CD62E+/CD42b-CD31+) levels were quantified by flow cytometry. RESULTS: Compared with non-smokers, healthy smokers and COPD smokers had elevated levels of circulating EMPs due to active pulmonary capillary endothelial apoptosis. Levels remained elevated over 12 months in healthy smokers and COPD smokers who continued smoking, but returned to non-smoker levels in healthy smokers who quit. In contrast, levels remained significantly abnormal in COPD smokers who quit. CONCLUSIONS: Pulmonary capillary apoptosis is reversible in healthy smokers who quit, but continues to play a role in COPD pathogenesis in smokers who progressed to airflow obstruction despite smoking cessation. TRIAL REGISTRATION NUMBER: NCT00974064; NCT01776398.

Socioeconomic Position and Premature Mortality in the AusDiab Cohort of Australian Adults.

OBJECTIVES: To determine the association of socioeconomic position indicators with mortality, without and with adjustment for modifiable risk factors. METHODS: We examined the relationships of 2 area-based indices and educational level with mortality among 9338 people (including 8094 younger than 70 years at baseline) of the Australian Diabetes Obesity and Lifestyle (AusDiab) from 1999-2000 until November 30, 2012. RESULTS: Age- and gender-adjusted premature mortality (death before age 70 years) was more likely among those living in the most disadvantaged areas versus least disadvantaged (hazard ratio [HR] = 1.48; 95% confidence interval [CI] = 1.08, 2.01), living in inner regional versus major urban areas (HR = 1.36; 95% CI = 1.07, 1.73), or having the lowest educational level versus the highest (HR = 1.64; 95% CI = 1.17, 2.30). The contribution of modifiable risk factors (smoking status, diet quality, physical activity, stress, cardiovascular risk factors) in the relationship between 1 area-based index or educational level and mortality was more apparent as age of death decreased. CONCLUSIONS: The relation of area-based socioeconomic position to premature mortality is partly mediated by behavioral and cardiovascular risk factors. Such results could influence public health policies.

Prevalence of disability in Australian elderly: Impact of trends in obesity and diabetes.

OBJECTIVE: We aimed to estimate the impact of past and future changes in obesity and diabetes prevalence in mid-life on disability prevalence for adult Australians. METHODS: We analysed data from the Australian Diabetes, Obesity and Lifestyle study (AusDiab) including participants aged 45-64years, disability-free at baseline (1999/2000) with disability information at follow-up (2011/12) (n=2107). We used coefficients from multinomial logistic regression to predict 10-year probabilities of disability and death from baseline predictors (age, sex, obesity, smoking, diabetes and hypertension). We estimated the prevalence of disability attributable to past (1980) and expected future (2025) changes in obesity and diabetes prevalence using the life table approach. RESULTS: We estimated that the prevalence of disability for those aged between 55 and 74years would have been 1697 cases per 100,000 persons less in 2010 (10.3% less) if the rates of obesity and diabetes observed in 2000 had been as low as the levels observed in 1980. However, if instead the prevalence of obesity and diabetes had been as high as the levels expected in 2025, then the prevalence of disability would have been an additional 2173 per 100,000 persons (an additional 13.2%). CONCLUSIONS: We demonstrate, for the first time, a substantial potential impact of obesity and diabetes trends on disability amongst those aged 55-74years. In Australian adults by 2025 we estimate that around 26% of disability cases would have been avoidable if there had been no change in obesity and diabetes prevalence since 1980. A similar impact is likely around the world in developed countries.

IL-17A and the Promotion of Neutrophilia in Acute Exacerbation of Chronic Obstructive Pulmonary Disease.

RATIONALE: Nontypeable Haemophilus influenzae (NTHi) causes acute exacerbation of chronic obstructive pulmonary disease (AECOPD). IL-17A is central for neutrophilic inflammation and has been linked to COPD pathogenesis. OBJECTIVES: We investigated whether IL-17A is elevated in NTHi-associated AECOPD and required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. METHODS: Experimental studies with cigarette smoke and NTHi infection were pursued in gene-targeted mice and using antibody intervention. IL-17A was measured in sputum collected from patients with COPD at baseline, during, and after AECOPD. MEASUREMENTS AND MAIN RESULTS: Exacerbated airway neutrophilia in cigarette smoke-exposed mice infected with NTHi was associated with an induction of IL-17A. In agreement, elevated IL-17A was observed in sputum collected during NTHi-associated AECOPD, compared with samples collected before or after the event. NTHi-exacerbated neutrophilia and induction of neutrophil chemoattractants over the background of cigarette smoke, as observed in wild-type mice, was absent in Il17a(-/-) mice and in mice treated with a neutralizing anti-IL-17A antibody. Further studies revealed that IL-1 receptor (R)1 signaling was required for IL-17A-dependent neutrophilia. Moreover, deficiency or therapeutic neutralization of IL-17A did not increase bacterial burden or delay bacterial clearance. CONCLUSIONS: IL-17A is induced during NTHi-associated AECOPD. Functionally, IL-1R1-dependent IL-17A is required for NTHi-exacerbated pulmonary neutrophilia induced by cigarette smoke. Targeting IL-17A in AECOPD may thus be beneficial to reduce neutrophil recruitment to the airways.