Indiana University-Purdue University Indianapolis (IUPUI) / Sensing, integrating, and relaying signals from the environment through proteins, metabolites, and lipids to the lung are critical for proper development. Moonlighting proteins, such as AIMP1, are a unique subset that serves at least two independent physiological functions. Encoded by gene AIMP1, AIMP1 has two known functions: (1) C-terminus EMAP II domain of full-length AIMP1 can be secreted out of the cell to chemoattract myeloid cells; (2) intracellular full-length protein interacts with tRNA synthetases in protein translation. However, despite the linkage of protein expression levels of with several lung pathologies such as bronchopulmonary dysplasia (BPD), effectively targeting the protein encoded by AIMP1 has been a challenge due to poorly understood mechanisms. This thesis explores physiological, signaling, and immunological moonlighting mechanisms of first, the extracellular EMAP II then the intracellular AIMP1. Experiments utilize both in vitro and in vivo models, including a murine model of BPD and Cre-mediated exon-deletion knockout. Experimental results provide evidence that in the BPD model, EMAP II levels are elevated and sustained – first in bronchial epithelial cells then in macrophages. Mice exposed to sustained and elevated EMAP II protein levels resemble the BPD phenotype while neutralization partially rescued the phenotype, implying EMAP II as a potential therapeutic target against BPD. Results from studies exploring EMAP II’s signaling mechanism identify transient stimulation of JAK-STAT3 phosphorylation, commonly found in inflammation-resolving macrophages. In contrast, it induces unique transcriptional changes that are reversible both by JAK-STAT inhibitor and siRNA-mediated knockdown of Stat3. Studies using AIMP1 knockout mouse reveal a novel function for the intracellular AIMP1. AIMP1 knockout mice exhibited neonatal lethality with a respiratory distress phenotype, decreased type I alveolar cell expression, and disorganized bronchial epithelium, suggesting a role in lung maturation. In vitro experiments suggest that a portion of AIMP1 residing in the cell’s membrane interacts with various phosphatidylinositols and contributes toward F-actin deposition and assembly. Data from these experimental studies provide insight into how the various functions of the promiscuous AIMP1 gene affect lung development. These studies exemplify not only characterize novel moonlighting mechanisms of AIMP1, but also highlight the importance of characterizing moonlighting proteins to promote therapeutic preventions. / 2020-02-21

Indiana University-Purdue University Indianapolis (IUPUI) / With urbanization, indoor exposure to microbial communities has changed significantly. While indoor bacterial exposure has decreased, indoor fungal exposure has increased. Along with increases in fungal species diversity, indoor air in urbanized countries is characterized by 1,000+ fold differences in mold spore density between buildings. Americans are estimated to spend ~87% of their lives in this new indoor environment, where airborne spore concentrations are unregulated. While the effects of mold exposure on certain respiratory diseases are well established, little is known about how inhaled mold affects extra-respiratory disease. Mold exposure is associated with central nervous system (CNS) symptoms in humans, but very little is known about how mold affects the CNS. Here, I show that subchronic inhalation of a common indoor mold, Aspergillus versicolor, causes neuroinflammatory gene transcription in five out of five brain regions tested, at both 1 and 2 days post inhalation. How peripheral inflammation from mold inhalation causes neuroinflammation is unknown. The mechanisms by which mold is inhaled and cleared implicate the lung, systemic circulation, and gastrointestinal tract as potential areas of immune response. After mold spores are inhaled and deposited in the lung, they are killed by antifungal immunity, cleared from the lung by the mucociliary escalator, swallowed, and excreted through the gastrointestinal tract. Molds produce many mycotoxins which enter enterohepatic recirculation with known toxic effects, including intestinal epithelial disruption. Mycotoxin concentrations in food are regulated in countries comprising ~85% of the world’s population. Inhaled molds produce these same mycotoxins, yet pulmonary exposure is unregulated. The multi-system effects of fungal exposure are poorly understood, and are part of a growing nascent field. Here, I discuss the current state of the indoor fungal environment, known health effects of mold exposure, how fungi activate the immune system, the CNS effects of a common indoor mold, how neuroinflammation from mold exposure might be occurring, future work needed for the systematic analysis of the CNS effects of mold, what is needed to determine the extent to which fungal exposure influences disease, and what might be done to mitigate those effects. / 2022-08-17

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19550号 / 医博第4057号 / 新制||医||1012(附属図書館) / 32586 / 京都大学大学院医学研究科医学専攻 / (主査)教授 坂井 義治, 教授 三嶋 理晃, 教授 開 祐司 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第20082号 / 医博第4175号 / 新制||医||1018(附属図書館) / 33198 / 京都大学大学院医学研究科医学専攻 / (主査)教授 小池 薫, 教授 湊谷 謙司, 教授 山下 潤 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第21627号 / 医博第4433号 / 新制||医||1033(附属図書館) / 京都大学大学院医学研究科医学専攻 / (主査)教授 平井 豊博, 教授 松原 和夫, 教授 羽賀 博典 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

This document only includes an excerpt of the corresponding thesis or dissertation. To request a digital scan of the full text, please contact the Ruth Lilly Medical Library's Interlibrary Loan Department (rlmlill@iu.edu).

A 65‐year‐old man presented with progessive dysphagia, which proved to be the first clinical manifestation of a periperal lung carcinoma (secondary to a submucosal metatasis in the esophagus). The lung tumor, hidden by the diaphragm on chest x‐ray, was not suspected until a thoracotomy was done. Although dysphagia is known to be the first manifestation of bron‐chogenic carcinomas, such presentation in a case of a peripheral lung carcinoma has not been well described. This case is reported with a review of the literature for cases with dysphagia secondary to a metastatic tumor in the esophagus.

No description available.

Common presenting symptoms of Lung cancer are cough, hemoptysis, chest pain, dyspnea, pleurisy. Dysphagia is a very uncommon presenting feature of Lung cancer. Incidence of Dysphagia in Lung cancer is unclear from Literature. Causes of Dysphagia in case of Lung cancer are Anatomically classified as Oropharyngeal and Esophageal. Causes of oropharyngeal dysphagia are oral candidiasis, oropharyngeal Metastasis of Lung cancer. Causes of esophageal dysphagia are Cervical or Mediastinal Lymphadenopathy, Motor dysfunction because of Brain stem Metastasis, Lambert eaton syndrome, Esophageal candidiasis, Radiation esophagitis. Here by we present an Unusual presentation of an aggressive disease, poorly differentiated SCLC presenting as Mid esophageal dysphagia secondary to extrinsic esophageal compression. 65 year old female with past medical history of Diabetes, Hypertension presented with complaints of worsening sub sternal chest pain radiating to back since last 2 days and progressive dysphagia. Pt underwent Left heart catheterization revealing non obstructive coronary artery disease. Modified Barium swallow showed stasis of contrast in mid esophagus, Endoscopy showed extrinsic compression of the proximal esophagus, normal mucosa. Computerized tomography of chest was done for further evaluation, revealing extensive left cervical, mediastinal, left hilar lymphadenopathy causing extrinsic compression of the esophagus and encasement of the left hilar structures. Further evaluation through Bronchoscopic biopsy of her left upper lobe mass reveals poorly differentiated small cell carcinoma. Staging was performed revealing limited stage disease. Started on concurrent chemotherapy with cisplatin, etoposide and radiation. As SCLC is highly responsive to chemotherapy and radiotherapy sensitive patient got symptomatic relief by the end of first cycle. SCLC is an aggressive lung cancer. As it is a micro metastatic disease in nature at presentation, it’s management is entirely different from Non SCLC. SCLC being an aggressive disease can cause dysphagia in 1-2% during the disease course. SCLC presenting as dysphagia is almost never reported in the literature. Our patient presented with severe dysphagia, described it as “a tennis ball sitting in her food pipe”. Fortunately she presented to the Emergency room with dysphagia and associated chest pain, we were able to make early diagnosis of SCLC, initiate treatment. Delay in the diagnosis lead to rapid progression of disease and poor prognosis. Through our case we wanted to convey that it is very important to obtain meticulous history, keeping broad differentials, which can help improve prognosis. Because not always the presenting features are from the organ of involvement it could be from the contiguous spread or compression.

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