Thesis (M.D.)--University of Hong Kong, 1992. / Includes bibliographical references (leaves 186-206) Also available in print.

published_or_final_version / Biochemistry / Master / Master of Philosophy

Thesis (M. Phil.)--University of Hong Kong, 2009. / Includes bibliographical references (p. 90-103). Also available in print.

published_or_final_version / abstract / toc / Biochemistry / Master / Master of Philosophy

Introduction: Bronchiectasis is a common chronic debilitating respiratory condition. Patients suffer daily cough, excess sputum production and recurrent chest infections because of inflamed and permanently damaged airways. The pathogenesis of bronchiectasis is poorly understood. Pulmonary pathology shows excess neutrophilic airways inflammation, but despite this over two thirds of patients are chronically infected with potential pathogenic microorganisms. The acute inflammatory response is a protective mechanism that is evolved to eliminate invading organisms and should ideally be self-limiting and lead to complete resolution. The driver for persistent neutrophilic airway inflammation in bronchiectasis is unknown, but infection is considered to play a major role. AIMS The main aims of this thesis were to: (i) Characterize neutrophils in the serum and airways in bronchiectasis in the stable state and during exacerbations; (ii) Cohort study to establish if LXA4 deficiency correlates with disease severity (iii) Characterize lipids in bronchiectasis airways and peripheral blood to establish the correlation of LXA4 to disease severity; (iv) To investigate a potential mechanism for low levels of LXA4 in bronchiectasis, lipoxin biosynthetic genes expression will be measured; (v) Assess the anti-inflammatory and pro resolution effect of LXA4 on neutrophils and monocyte derived macrophages from healthy volunteers; (vi) Assess the anti-inflammatory and pro resolution effect of LXA4 on neutrophils during exacerbations in bronchiectasis and community acquired pneumonia. Methods (I) To establish the serum neutrophil subtype in stable state and following antibiotic treatment in patients with bronchiectasis, the following studies were done. Inclusion criteria: Patients aged 18-80 were recruited. All had an established radiological diagnosis of bronchiectasis (CT of the chest). Patients had clinically significant bronchiectasis, aetiology being either idiopathic or post infection. Exclusion Criteria: current smokers or ex-smokers of less than 1 year; >20 pack year history; cystic fibrosis; active allergic bronchopulmonary aspergillosis; active tuberculosis; poorly controlled asthma; severe COPD requiring nebulised bronchodilators or long term oxygen therapy; patients on aspirin or leukotriene inhibitors, pregnancy or breast feeding, active malignancy. A. 6 patients with mild bronchiectasis, 6 patients with severe bronchiectasis and 6 healthy volunteers were recruited. Serum and airways neutrophils were subsequently isolated. Neutrophil apoptosis, CD11b and CD62L expression, myeloperoxidase release, superoxide generation, phagocytosis and killing of GFP labeled bacteria were assessed. B. To compare serum with airways neutrophils function, bacterial phagocytosis and killing of GFP labeled bacteria was done, with both serum and airways neutrophils. Samples were obtained from the above group of patients. C. To establish neutrophil function following antibiotic treatment, 6 bronchiectasis patients at the beginning (day1) and the end (day14) of intravenous antibiotic therapy for an exacerbation were studied. As a control group, 6 community acquired pneumonia patients at the beginning (day1) and the end (day 5) of intravenous antibiotic therapy for infection were studied. Induced sputum and peripheral blood was taken at day1 and 5, where able. Phagocytosis and killing of GFP labeled bacteria was assessed and the two groups compared. (II) To address if lipoxin A4 deficiency correlates with disease severity, a cohort study was done in bronchiectasis patients. 169 patients were recruited and followed up for 1 year. Assessments done were Bronchiectasis severity index, systemic inflammatory markers (white cell count, ESR and c-reactive protein), Forced Expired Volume in 1sec, Forced Vital Capacity and its ratio, antibiotic courses in 1 year, hospital admissions in 1 year, sputum microbiology, quality of life assessments by Leicester Cough Questionnaire and St. Georges Respiratory Questionnaire, interleukin 8, myeloperoxidase, neutrophil elastase and leukotriene B4 (from sputum). (III) To assess effect of lipoxin on disease severity, 6 healthy volunteers, 10 patients with mild disease, 15 with moderate and 9 with severe disease were recruited. Disease severity was calculated as per the bronchiectasis severity index. All participants had 60mls of blood taken and underwent a bronchoscopy. Two segments of the lungs were washed out from bronchiectasis patients, an area affected by bronchiectasis and an area unaffected by bronchiectasis. This led to patients acting as their own internal control. Serum and airways neutrophils (from both segments) were subsequently isolated. Assessments done were systemic inflammatory markers (white cell count, ESR and c-reactive protein), serum lipoxin A4 and the cathelicidin LL-37, Forced Expired Volume in 1sec, Forced Vital Capacity and its ratio, transfer factor for carbon monoxide, antibiotic courses in 1 year, hospital admissions in 1 year and sputum microbiology. Phagocytosis and bacterial killing were assessed by both serum and airways neutrophils. From bronchoalveolar lavage fluid (BALF), I measured myeloperoxidase and neutrophil elastase. For both serum and BALF, lipidomics were obtained. (IV) To address the impact of anatomic compartment, gene expression was measured in from endobronchial brushings from the same cohort of bronchiectasis patients and controls as above, where samples were available. qPCR was performed for the following eicosanoid biosynthetic genes- 5 Lipoxygenase (LOX), 15 LO-A, 15LO-B and leukotriene (LT) A4 hydrolase. (V) To assess the anti inflammatory and pro resolution effect of LXA4 on neutrophils and monocyte derived macrophages from healthy volunteers, freshly isolated PMN will be treated with LXA4 or vehicle control. Spontaneous apoptosis was measured. fMLF and cytochalasin B was added and the inflammatory response assessed measuring myeloperoxidase (MPO), free neutrophil elastase (NE), CD11b, CD18 and CD62L. Human monocytes and PMNs were isolated from bronchiectasis patients. Following differentiation, LXA4 treated or control adherent, washed MDMs will be incubated with apoptotic stained PMNs. Efferocytosis was analyzed by flow cytometry. (VI) To establish the effect of Lipoxin A4 on neutrophil function following antibiotic treatment, the same study group used to evaluate aim 1 was taken. As a control group, 6 community acquired pneumonia patients at the beginning (day1) and the end (day 5) of oral or intravenous antibiotic therapy for infection were studied. Induced sputum and peripheral blood was taken at day1 and 5, where able. Phagocytosis and killing of GFP labeled bacteria and the effect of Lipoxin A4 was assessed and the two groups compared. Serum and sputum lipidomics were obtained in bronchiectasis exacerbations on day 1 and day 14. Serum lipidomics was obtained in pneumonia on day 1 and day 5. RESULTS (I) Neutrophil sub type study (Studied on healthy volunteers/ mild/ severe bronchiectasis) Peripheral blood neutrophils from bronchiectasis patients showed that there was significantly more viable neutrophils in mild and severe bronchiectasis compared to healthy volunteers, p=0.002 and p=0.005 respectively. In addition, there was significantly less apoptotic neutrophils in mild and severe bronchiectasis compared to healthy volunteers, p=0.0003 and p < 0.0001 respectively. There was a significantly higher level of CD11b in the mild (p=0.01) and severe bronchiectasis (p=0.01) compared to healthy volunteers. There was more CD62L shedding (p=0.02) and myeloperoxidase release (p=0.04) in bronchiectasis compared to healthy volunteers. There was lesser phagocytosis in mild (p=0.04) and severe (p=0.03) bronchiectasis compared to healthy volunteers. This led to lesser bacterial killing in mild (p=0.04) and severe (p=0.0004) bronchiectasis compared to healthy volunteers.

published_or_final_version / abstract / toc / Biochemistry / Doctoral / Doctor of Philosophy

Thesis (M. Res.)--University of Hong Kong, 2006.

Disrupted sleep and nocturnal hypoxia are common in cystic fibrosis (CF). However, the predictors of nocturnal hypoxia in CF are still controversial. In order to identify the risk factors for nocturnal desaturation and sleep disturbances, we carried out a clinical and polysomnographic investigation of CF patients. We studied 30 clinically stable CF cases with clinical lung disease (mean age=12.8; mean forced expiratory volume in 1 second FEV1=65.2), 10 CF cases without significant lung disease (mean age=13.3; mean FEV1=99.8), and 20 controls (mean age=15.5). Patients were evaluated by spirometry, 6-min walk test (6MWT), the ShwachmanâKulczycki (SâK) score, and full overnight polysomnography. Cases with clinical lung disease had lower body mass index, forced vital capacity, and SâK scores. During sleep, five CF cases with clinical lung disease (15%) had SaO2 <90% during more than 30% of total sleep timeand 11 cases (36.6%) had a nadir SaO2 below 85%. FEV1 values for CF cases with clinical lung disease were related to nadir SaO2 (P<0.03) and to mean oxygen saturation SaO2 (P=0.02). A receiver operating characteristic (ROC) analysis determined FEV1 at 64% to be predictive of nocturnal desaturation as defined by minimum SaO2 <85% (sensitivity=92.3%; specificity=77.3%) or SaO2<90% for 30% of sleep time (sensitivity=81.8%; specificity=85.2%). Frequency of impaired sleep was not different in CF cases with (N=5) and without significant lung disease (N=2, P=0.53). Sleep architecture was not significantly different between the two groups. Sleep apnea was present in three CF cases with clinical lung disease and in one case without significant lung disease. In summary, desaturation during sleep can be predicted by FEV1<64%with good sensitivity and specificity. There are no significant differences in sleep architecture between clinically stable CF cases with and without significant lung disease. The recognition of biological markers that can predict clinical deterioration in cystic fibrosis (CF) is a key issue in everyday care of these patients. The (S-K) scores and (FEV1) have been considered the best independent predictors of impairment/disability. The aim of this study was to evaluate the role of high-resolution computed tomography of the chest (HRCT) and the use of the Bhalla score in the detection of functional disability in CF. Cases of both genders, aged older than six years, with CF clinically stable were studied with spirometry, basal oxygen saturation SpO2, the 6MWT, HRCT and the S-K score. Twenty-five patients (15 male, mean age 14.2Â5.6) with FEV1 (range 28.6-98.0; mean 62.5Â21.8) were studied. Nine patients had severe/moderate respiratory insufficiency (40<FEV1&#8804;59), nine had mild (59<FEV1&#8804;79) and six had normal function (FEV1>79). Bronchiectasis was the most frequent finding. Peribronchial thickening, mucus plugging and emphysema, despite being less severe, were also commonly observed. None of the cases presented bullae. Total scores of CT abnormalities varied from 7 to 25 (13.8Â4.4). The ROC curve showed the high sensitivity/specificity for Bhalla and S-K scores in the prediction of clinical disability as measured by the FEV1. By comparison, the Bhalla scores showed higher sensitivity than the S-K scores. SpO2 and the 6MWT were not good predictors of disability as measured by functional pulmonary tests. Melatonin, a natural hormone secreted by the pineal gland, has an important function in the synchronization of circadian rhythms, including the sleepâwake cycle, and has been shown to possess significant anti-oxidant properties. To evaluate the effects of exogenous melatonin on sleep and inflammation and oxidative stress markers in CF we conducted a randomized double-blind placebo controlled study initially involving 20 patients with CF. One case failed to conclude the study. All subjects were clinically stable when studied and without recent infectious exacerbation or hospitalization in the last 30 days. Groups were randomized for placebo (N= 10; mean age 12.10Â6.0) or melatonin 3.0 mg (N=9; mean age 16.62Â8.26) during 21 days. Actigraphy was performed during 6 days before start of medication and in the third week (days 14 to 20) of treatment. Isoprostane and nitrite levels were determined in exhaled breath condensate (EBC) at baseline (day 0) and after treatment (Day 21). Melatonin improved sleep efficiency (p=0.01) and tended to improve sleep latency (p= 0.08). Melatonin reduced EBC nitrite (p=0.01) but not isoprostane. In summary, melatonin administration reduces nitrite levels in EBC and improves sleep measures in clinically stable CF patients. / A Fibrose CÃstica (FC) à uma doenÃa crÃnica e progressiva acompanhada por episÃdios repetidos de infecÃÃes respiratÃrias. Neste trabalho, realizaram-se investigaÃÃes relacionadas aos aspectos polissonogrÃficos, de tomografia computadorizada de alta resoluÃÃo do tÃrax (TCAR) e um estudo sobre os efeitos da melatonina em pacientes com FC, que serÃo descritos a seguir. Na FC, as alteraÃÃes do sono e a dessaturaÃÃo noturna da oxi-hemoglobina sÃo comuns, no entanto, os preditores dessa dessaturaÃÃo ainda sÃo controversos e a indicaÃÃo para a realizaÃÃo de polissonografia ainda nÃo foi definida. Com o objetivo de identificar os fatores de risco associados com hipÃxia noturna e com as alteraÃÃes do sono, realizou-se uma investigaÃÃo clÃnica e polissonogrÃfica de pacientes com FC com e sem envolvimento pulmonar. Trata-se de um estudo transversal de pacientes clinicamente estÃveis com (N=30; mÃdia de idade = 12,8 anos; mÃdia de volume expiratÃrio forÃado no primeiro segundo (VEF1= 65,2%) e sem (N=10; mÃdia de idade =13,3; mÃdia de VEF1 = 99,8%) doenÃa pulmonar e controles (N=20; mÃdia de idade =15,5). Os pacientes foram avaliados por meio das provas de funÃÃo pulmonar (PFP), teste da caminhada de seis minutos (TC6min), pelo escore Swhachman-Kulczycki (S-K) e polissonografia de noite inteira. Os pacientes com doenÃa pulmonar apresentavam Ãndices mais baixos de massa corpÃrea, VEF1, capacidade vital forÃada e escore S-K. Durante o sono, entre os pacientes com FC e doenÃa pulmonar, cinco (15%) tinham SpO2 <90% durante mais de 30% do tempo total de sono e 11 (36,6%) tinham SpO2 mÃnima. Observou-se uma correlaÃÃo entre os nÃveis de VEF1 e os nÃveis mÃdios de SpO2 (p=0,02) e valores mÃnimos da SpO2 (p<0,03). A Receiver Operating Curve (ROC) mostrou que o VEF1 < 64% à um preditor da dessaturaÃÃo noturna ao se considerar o nadir, SpO2 menor que 85% (sensibilidade = 92,3% e especificidade = 77,3%) ou SpO2 < 90% durante mais de 30% (sensibilidade = 81,8% e especificidade = 85,2%). A frequÃncia das alteraÃÃes do sono, quando se considerou a qualidade subjetiva do sono (IQSP), nÃo foi diferente entre os casos de FC com (N=5) e sem comprometimento pulmonar (N=2, P=0.53). A arquitetura do sono nÃo foi significativamente diferente entre os casos de FC com e sem doenÃa pulmonar. Apneia obstrutiva do sono estava presente em trÃs casos com doenÃa pulmonar e em um caso sem doenÃa pulmonar. Em conclusÃo, a dessaturaÃÃo durante o sono pode ser prevista por um VEF1 < 64% com boa sensibilidade e especificidade. NÃo hà diferenÃas significantes entre os casos de FC clinicamente estÃveis com e sem envolvimento pulmonar. Sugere-se que a polissonografia pode ser Ãtil em casos selecionados de FC com e sem doenÃa pulmonar quando hà suspeita de apneia obstrutiva do sono. Em relaÃÃo ao estudo com TCAR do tÃrax, deve ser enfatizado que o reconhecimento de marcadores de gravidade, capazes de predizer a deterioraÃÃo clÃnica na fibrose cÃstica à de fundamental importÃncia para o manuseio terapÃutico dos pacientes. O escore de S-K e o VEF1 sÃo considerados os melhores preditores independentes do prognÃstico em FC. O objetivo desse estudo foi avaliar o papel da TCAR e o escore de Bhalla na avaliaÃÃo da gravidade de pacientes com FC. Casos de ambos os sexos, com idade superior a seis anos, clinicamente estÃveis, foram avaliados mediante espirometria, nÃveis basais de saturaÃÃo de oxigÃnio (SpO2), TC6min, TCAR e escores S-K e Bhalla. Vinte e cinco pacientes (15 homens, idade mÃdia 14,2  5,6) com VEF1 (variaÃÃo 28,6-98,0; mÃdia 62,5  21,8) foram estudados. Nove pacientes apresentavam insuficiÃncia respiratÃria moderada/grave (40 < VEF1 &#8804; 59), nove tinham insuficiÃncia respiratÃria leve (59 < VEF1 &#8804; 79) e seis tinham funÃÃo normal (VEF1 > 79). As bronquiectasias foram o achado tomogrÃfico mais frequente. Espessamento peribrÃnquico, rolha de muco e enfisema, apesar de menor gravidade, foram tambÃm comumente observados. Nenhum dos casos apresentava bolhas. Os escores totais das anormalidades tomogrÃficas variaram de 7 a 25 (13,8  4,4). A curva (ROC) mostrou alta sensibilidade/especificidade para o escore Bhalla na prediÃÃo da gravidade da doenÃa medida pelo VEF1. De forma comparativa, os escores Bhalla apresentaram maior sensibilidade do que os escores S-K. Os nÃveis basais de SpO2 e o TC6min nÃo foram bons preditores de gravidade avaliada pelos testes de funÃÃo pulmonar. Realizou-se um estudo sobre os efeitos da melatonina na FC. A melatonina à um hormÃnio natural secretado pela glÃndula pineal, tem uma funÃÃo importante na sincronizaÃÃo do ritmo circadiano, incluindo o ciclo vigÃlia-sono e tem propriedades antioxidantes. Com o objetivo de avaliar os efeitos da melatonina no sono, na inflamaÃÃo e no estresse oxidativo pulmonar realizou-se um estudo randomizado, duplo-cego e controlado por placebo. Vinte pacientes com FC foram inicialmente avaliados. Um paciente nÃo concluiu o estudo. Todos os indivÃduos estavam clinicamente estÃveis por ocasiÃo do estudo, ou seja, nÃo tinham apresentado exacerbaÃÃes infecciosas ou hospitalizaÃÃes nos Ãltimos 30 dias. Os grupos foram randomizados para o uso de placebo (N= 10; mÃdia da idade 12,10  6,0) ou melatonina 3,0 mg (N=9; mÃdia da idade 16,62  8,26) durante 21 dias. Um registro actigrÃfico foi realizado durante seis dias, antes do inÃcio da medicaÃÃo e na terceira semana (dias 14 a 20) do tratamento. Os nÃveis de isoprostano e nitrito foram determinados no condensado de ar exalado (CAE) no inÃcio do estudo (dia 0) e depois do tratamento (dia 21). A melatonina melhorou a eficiÃncia do sono (p=0,01) e nitrito do CAE, porÃm nÃo reduziu o isoprostano. Em conclusÃo, em pacientes com FC clinicamente estÃveis, a administraÃÃo de melatonina reduz os nÃveis de nitrito e melhora os parÃmetros de sono.

Orientadores: Ilma Aparecida Paschoal, Mônica Corso Pereira / Tese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas / Made available in DSpace on 2018-08-26T20:34:20Z (GMT). No. of bitstreams: 1 Veronez_LilianideFatima_D.pdf: 6581224 bytes, checksum: 21912792a141bd85146488626d2e9e24 (MD5) Previous issue date: 2014 / Resumo: As doenças pulmonares obstrutivas de diferentes etiologias se apresentam com envolvimento progressivo das vias aéreas periféricas. As vias aéreas periféricas, conhecidas como zona silenciosa do pulmão, não são adequadamente avaliadas com testes convencionais de função pulmonar. O princípio do gás "washout" eliminação de gases tem sido utilizado para detectar heterogeneidade da ventilação pulmonar e para estimar a localização do processo da doença subjacente. A capnografia volumétrica (CV) analisa o padrão de eliminação de CO2 como uma função do volume expirado. Objetivo: medir os "slopes" da fase 3 normalizados pelo volume corrente expiratório em pacientes com bronquiectasia não-fibrose cística (BQNF ) e em pacientes com bronquite crônica tabágica obstrutiva (BCTO), a fim de comparar os slopes obtidos para os grupos. Métodos: Pacientes com BQNF e com BCTO foram incluídos sequencialmente a partir dos ambulatórios de Insuficiência Respiratória Crônica do HC-Unicamp. Um grupo controle foi estabelecido para grupo BQNF, pareados por sexo e idade. Todos os indivíduos realizaram espirometria, CV e teste da caminhada dos seis minutos (TC6). Duas comparações foram feitas: grupo BQNF vs o grupo controle, e BQNF vs o grupo BCTO. O projeto foi aprovado pelo comitê de ética da nossa instituição. Os testes estatísticos utilizados foram Wilcoxon ou teste t de Student diferenças estatisticamente significativas foram consideradas com p < 0,05. Resultados: na comparação do grupo BQNF (N = 20) vs grupo controle (N = 20), foram encontradas diferenças significativas no IMC e em diversas variáveis funcionais (espirometria, CV, TC6) com os piores resultados observados no grupo BQNF. Na comparação entre o grupo BCTO (N = 20) vs grupo BQNF, embora os pacientes com BCTO tivessem piores valores na espirometria e TC6, as variáveis capnograficas Slp2, Slp3/Ve e Slp3/EtCO2 foram semelhantes. Conclusão: Estes resultados podem indicar que as curvas de eliminação de gás não são suficientemente sensíveis para monitorizar a gravidade das anormalidades estruturais. O papel do slope normalizado da fase 3 pode se explorado como o mais sensível índice de doença das pequenas vias aéreas, embora possa não ser igualmente sensível em discriminar a gravidade das alterações / Abstract: Background: Obstructive lung diseases of different etiologies present with progressive peripheral airway involvement. The peripheral airways, known as silent lung zone, are not adequately evaluated with conventional function tests. The principle of gas washout has been used to detect pulmonary ventilation inhomogeneity and to estimate the location of the underlying disease process. Volumetric capnography (VC) analyses the pattern of CO2 elimination as a function of expired volume. Objective: to measure normalized phase 3 slopes with VC in patients with non-cystic fibrosis bronchiectasis (NCB) and in bronchitic patients with chronic obstructive pulmonary disease (COPD) in order to compare the slopes obtained for the groups. Methods: NCB and severe COPD were enrolled sequentially from an outpatient clinic (Universitary Hospital). A control group was established for NCB group, paired by sex and age. All subjects performed spirometry, VC and Six-Minute Walk Test (6MWT). Two comparisons were made: NCB group vs its control group, and NCB group vs COPD group. The project was approved by the ethical committee of the institution. Statistical tests used were Wilcoxon or Student t-test; statistically significant difference considered with p<0.05. Results: Concerning NCB group (N=20) vs control group (N=20), significant differences were found in BMI and in several functional variables (spirometric, CV, 6MWT) with the worse results observed in NCB group. In the comparison between the COPD group (N=20) vs NCB group, although patients with COPD have had worse spirometric and 6MWT values, the capnographic variables Slp2, Slp3/Ve and Slp3/EtCO2 were similar. Conclusion: These findings may indicate that the gas elimination curves are not sensitive enough to monitor the severity of structural abnormalities. The role of normalized phase 3 slope may be worth explore as a more sensitive index of small airway disease, even though it may not be equally sensitive in discriminating the severity of the alterations / Doutorado / Clinica Medica / Doutora em Clínica Médica

High-resolution computed tomography (HRCT) of the chest is commonly used in the diagnosis of a variety of lung diseases. Structural changes associated with clinical characteristics of disease may also define specific disease-associated physiologic states that may provide insights into disease pathophysiology. Gene expression profiling is potentially a useful adjunct to HRCT to identify molecular correlates of the observed structural changes. However, it is difficult to directly access diseased distal airway or lung parenchyma routinely for profiling studies. Previously, we have profiled bronchial airway in normal-appearing epithelial cells at the mainstem bronchus, detecting distinct gene expression alterations related to the clinical diagnosis of chronic obstructive pulmonary disease (COPD) and lung cancer. These gene expression alterations offer insights into the molecular events related to diseased tissue at more distal airways and in the parenchyma, which we hypothesize are due to a field-of-injury effect. Here, we expand this prior work by correlating airway gene expression to COPD and bronchiectasis phenotypes defined by HRCT to better understand the pathophysiology of these diseases. Additionally, we classified pulmonary nodules as malignant or benign by combining HRCT nodule imaging characteristics with gene expression profiling of the nasal airway. First, we collected brushing samples from the main-stem bronchus and assessed gene expression alterations associated with COPD phenotypes defined by K-means clustering of HRCT-based imaging features. We found three imaging clusters, which correlated with incremental severity of COPD: preserved, interstitial predominant, and emphysema predominant. 357 genes were differentially expressed between the normal and the emphysema predominant clusters. Functional analysis of the differentially expressed genes suggests a possible induction of inflammatory processes and repression of T-cell related biologic pathways, in the emphysema predominant cluster. We then discovered gene expression alterations associated with radiographic evidence of bronchiectasis (BE), an underdiagnosed obstructive pulmonary disease with unclear pathophysiology. We found 655 genes were differentially expressed in bronchial epithelium from individuals with radiographic evidence of BE despite none of the study participants having a clinical BE diagnosis. In addition to biological pathways that had been previously associated with BE, novel pathways that may play important roles in BE initiation were also discovered. Furthermore, we leveraged an independent single-cell RNA-sequencing dataset of the bronchial epithelium to explore whether the observed gene expression alterations might be cell-type dependent. We computationally detected an increased presence of ciliated and deuterosomal cells, as well as a decreased presence of basal cells in subjects with widespread radiographic BE, which may reflect a shift in the cellular landscape of the airway during BE initiation. Finally, we identified gene expression alterations within the nasal epithelium associated with the presence of malignant pulmonary nodules. A computational model was constructed for determining whether a nodule is malignant or benign that combines gene expression and imaging features extracted from HRCT. Leveraging data from single-cell RNA sequencing, we found genes increased in patients with lung cancer are expressed at higher levels within a novel cluster of nasal epithelial cells, termed keratinizing epithelial cells. In summary, we leveraged gene expression profiling of the proximal airway and discovered novel biological pathways that potentially drive the structural changes representative of physiologic states defined by chest HRCT in COPD and BE. This approach may also be combined with chest HRCT to detect weak signals related to malignant pulmonary nodules. / 2024-02-03T00:00:00Z