Thesis (Ph. D.)--Virginia Polytechnic Institute and State University, 1990. / Vita. Abstract. Includes bibliographical references (leaves 194-221). Also available via the Internet

Thesis (Ph.D.)--Aberdeen University, 2008. / Title from web page (viewed on Mar. 9, 2009). Includes bibliographical references.

Thesis--Wisconsin. / Vita. Includes bibliographical references (leaves 125-148).

The effect of lysolecithin on the macrophage was studied using five macrophage function assays. The results of indicate that lyso lecithin is a macrophage activating agent which causes enhanced cell spreading, increased phagocytosis of sheep erythrocytes, heightened membrane activity in the presence of damaged autologous red blood cells, chemotaxis, and vigorous phagocytosis and intracellular killing of Staphylococcus albus.

L'alcool est la première cause de maladie hépatique en France, et la maladie alcoolique du foie est responsable de près de 7000 décès par an. La surcharge graisseuse est la troisième cause de maladie hépatique, et s'inscrit dans le cadre plus large du syndrome métabolique. La physiopathologie de ces deux types de maladies hépatiques est très similaire. La stéatose, définie par l'accumulation excessive de triglycérides dans le foie, est la première lésion retrouvée chez les patients. La stéatose peut évoluer vers la stéato‐hépatite lorsqu'elle est associée à une inflammation, une mort hépatocytaire, et à l'initiation d'une réponse fibrogénique. La stéato‐hépatite évolue parfois vers la cirrhose, stade ultime avant le carcinome hépatocellulaire. Il n'existe à ce jour aucun traitement efficace de ces maladies hormis le sevrage alcoolique dans le cadre de la maladie alcoolique du foie et un régime associé à de l'exercice dans le cadre de la maladie hépatique d'origine non‐alcoolique. Il est donc urgent d'identifier de nouvelles stratégies thérapeutiques pour lutter contre la progression de ces maladies.L'activation des cellules de Küpffer, les macrophages résidents du foie, joue un rôle déterminant dans le processus inflammatoire qui initie l'atteinte hépatique. Comme tous les macrophages, les cellules de Küpffer peuvent adopter tout un spectre de phénotypes parmi lesquels on distingue deux extrêmes : le phénotype M1 ou pro‐inflammatoire et le phénotype M2 ou anti‐inflammatoire. Les données de la littérature ainsi que celles préalablement obtenues par le laboratoire d'accueil ont établi les effets délétères d'une polarisation pro‐inflammatoire M1 des cellules de Küpffer sur l'évolution de la maladie hépatique d'origine alcoolique ou non alcoolique. Cependant, aucune étude n'avait examiné l'impact d'une polarisation anti‐inflammatoire (M2) des cellules de Küpffer sur ces maladies.L'objectif de ce travail a été d'évaluer si favoriser la polarisation des cellules de Küpffer vers un phénotype M2 anti‐inflammatoire pouvait limiter la progression des maladies hépatiques d'origine alcoolique ou non alcoolique.Afin de mener à bien ce projet, nous avons combiné l'utilisation de modèles murins de maladie hépatique d'origine alcoolique ou non alcoolique, des approches pharmacologiques et des expériences sur cellules isolées. Ces études ont été complétées par des données obtenues sur des biopsies humaines.Ce travail a permis de démontrer que favoriser la polarisation M2 des cellules de Küpffer protège le foie de la stéatose, de la mort hépatocytaire et de l'inflammation. Ces résultats identifient un nouveau mécanisme anti‐inflammatoire déclenché par les cellules de Küpffer polarisées M2 : l'induction sélective de l'apoptose des cellules de Küpffer polarisées M1. Ce travail ouvre de nouvelles perspectives à l'identification de stratégies pour limiter la progression des maladies hépatiques et pourrait également avoir des retombées plus larges dans le cadre d'autres maladies chroniques inflammatoires ciblant d'autres tissus que le foie. / Summary not transmitted

by Suen Yick-keung. / "July 1999." / Thesis (Ph.D.)--Chinese University of Hong Kong, 1999. / Includes bibliographical references (p. 255-273). / Electronic reproduction. Hong Kong : Chinese University of Hong Kong, [2012] System requirements: Adobe Acrobat Reader. Available via World Wide Web. / Mode of access: World Wide Web. / Abstracts in English and Chinese.

子宮內膜異位症是一種常見的，但複雜的婦科疾病，發病機制不明。它的特點是異位生长的子宮內膜組織。目前已提出多种發病機制的相关理論。现广泛接受經典的Sampson经血逆行的理論，，子宮內膜細胞出现在腹腔中。然而，对于子宮內膜異位症的發展中出现的細胞和分子事件却研究甚少。血管生成在早期子宮內膜異位病灶的生長和发展中起關鍵作用。在缺氧條件下，低灌注的異位子宮內膜組織促进血管形成因子被激活，以建立新的血管來提供氧和營養物質。血管生成的確切病理機制目前仍不清楚。我們推測，氧化應激是子宮內膜異位症的血管生成和發展的關鍵。目前的研究只是表明氧化應激可能促進子宮內膜細胞的生長和粘附，加剧子宮内膜异位症。但是，子宮內膜異位症的氧化應激具体機制仍不清楚。 / 在這項研究中，我們旨在了解氧化應激在子宮內膜異位症的早期血管生成和發展的重要作用。我们利用實驗性子宮內膜異位症小鼠模型用来研究子宮内膜异位症潛在的氧化應激機制。活体成像显示在子宮內膜异位植入后2 -6小時可检测到高活性氧簇（ROS）。同時，植入位处的也可见巨噬細胞浸潤和HIF-1α的表達。緊接著1天之內血管生成細胞因子表達上調，植入后一周后即有新血管形成。這表明巨噬細胞可能在子宮內膜異位症的早期發展中啟動氧化應激和促進血管生成。為了驗證在氧化應激，血管生成，子宮內膜異位癥的發展中巨噬細胞的作用，，採用抗F4/80抗體造成巨噬細胞功能缺失和12/15 LOX基因敲除小鼠模型下的氧化應激失調兩種模型進行研究。 通過干擾和破壞巨噬細胞介導的氧化應激，在子宮內膜植入處ROS產物生成顯著減少。血管生成因子受到抑制且血管發育不全。子宮內膜異位病灶均小於對照組。這表明巨噬細胞是氧化應激中重要介質。他們在促進子宮內膜異位症的早期血管生成和發展中起重要作用。由PX-478，HIF-1α抑製劑介導的治療也在子宮內膜異位症模型中進行更深入地研究。在血管生成途徑中抑制HIF-1α可減小病灶的大小和抑制新血管形成，但不影響巨噬細胞浸潤和子宮內膜植入物中的活性氧的生產。這表明巨噬細胞和ROS作用於子宮內膜異位症的血管形成機制的上游。總之，我們證明了巨噬細胞介導的氧化應激在子宮內膜異位症的早期血管生成和發展中起重要作用。 / Endometriosis is a common but complex gynecological disorder of unknown pathogenesis. It is characterized by ectopic growth of endometrial tissues Many theories have been proposed to the pathogenesis of endometriosis. The classical Sampson’s theory of retrograde menstruation is widely accepted to determine the presence of endometrial cells in the peritoneal cavity. However, little is known on the cellular and molecular events in the development of endometriosis. Angiogenesis plays a key step in the early growth and survival of the endometriotic lesions. Under hypoxic condition, pro-angiogenic factors are activated in poorly perfused ectopic endometrial tissues in order to establish new blood vessel to supply oxygen and nutrients. The precise pathological mechanisms of this angiogenesis pathway are still unclear. We hypothesized that oxidative stress is critical for the angiogenesis and development of endometriosis. Current studies only suggested oxidative stress may increase growth and adhesion of endometrial cells, promoting endometriosis. However, the underlying mechanism of oxidative stress in endometriosis remains unclear. / In this study, we aimed to understand the important role of oxidative stress in early angiogenesis and development of endometriosis. Experimental endometriosis mouse model was used to determine the underlying mechanism of oxidative stress. By in vivo imaging, high reactive oxygen species (ROS) production in the endometrial implants was detected from 2 -6 hours of transplantation. Concurrently, macrophage infiltration and HIF-1α expression in the implants were anticipated. Subsequently, angiogenic cytokines were upregulated within 1 day and new blood vessels were formed at least 1 week after transplantation. This suggested that macrophage may initiate the oxidative stress surge and angiogenesis pathway in early development of endometriosis. To confirm the role of macrophage in the oxidative stress, angiogenesis and development of endometriosis, macrophage depletion by anti-F4/80 antibody and oxidative stress disruption by 12/15 Lox transgenic knockout mice were employed in the experimental endometriosis models. By depleting macrophage and disrupting macrophage to mediate oxidative stress, the ROS production was significantly decreased in the endometrial implants. Angiogenesis factors were suppressed and blood vessels were under-developed. The endometriotic lesions were smaller than control. This showed macrophage is the key mediator of oxidative stress. They played an important role on promoting early angiogenesis and development of endometriosis. Potential therapeutic treatment by PX-478, a HIF-1α inhibitor, was further investigated in the experimental endometriosis model. Inhibition of HIF-1α in the angiogenic pathway decrease the lesion size and new vessel formed, but macrophage infiltration and ROS production in the endometrial implants was not affected. This suggested that macrophage and ROS are the upstream mechanism of the angiogenic pathway in endometriosis. In conclusion, we demonstrated that oxidative stress mediated by macrophages play an important role in the early angiogenesis and development of endometriosis. / Detailed summary in vernacular field only. / Detailed summary in vernacular field only. / Man, Chi Wai. / Thesis (Ph.D.)--Chinese University of Hong Kong, 2013. / Includes bibliographical references (leaves 66-82). / Abstracts also in Chinese. / Title --- p.i / Acknowledgment --- p.ii / List of publication and conferences --- p.iv / Additional achievements --- p.v / Abbreviations --- p.vi / Table of Contents --- p.viii / List of Figures --- p.xiii / List of Tables --- p.xviii / Abstract --- p.xix / Chinese Abstract --- p.xxi / Chapter Chapter 1. --- Endometriosis / Chapter 1.1. --- Definition of Endometriosis --- p.1 / Chapter 1.1.1. --- Treatment of Endometriosis --- p.2 / Chapter 1.1.1.1. --- Expectant Management --- p.2 / Chapter 1.1.1.2. --- Medical Therapy --- p.2 / Chapter 1.1.1.2.1. --- Analgesics --- p.2 / Chapter 1.1.1.2.2. --- Hormones --- p.3 / Chapter 1.1.1.3. --- Surgery --- p.4 / Chapter 1.1.1.3.1. --- Surgical Treatment --- p.4 / Chapter 1.1.1.3.2. --- Conservative Surgery --- p.4 / Chapter 1.1.1.3.3. --- Definitive Surgery --- p.5 / Chapter 1.1.2. --- Pathogenesis and Pathophysiology of Endometriosis --- p.5 / Chapter 1.2. --- Oxidative stress --- p.7 / Chapter 1.2.1. --- Pro-oxidants --- p.7 / Chapter 1.2.2. --- Antioxidants --- p.8 / Chapter 1.2.2.1. --- Non-enzymatic Antioxidants --- p.9 / Chapter 1.2.2.2. --- Enzymatic Antioxidants --- p.9 / Chapter 1.2.2.2.1. --- Superoxide Dismutase --- p.10 / Chapter 1.2.2.2.2. --- Catalase --- p.10 / Chapter 1.2.2.2.3. --- Peroxiredoxins --- p.11 / Chapter 1.2.2.2.4. --- Glutathione Peroxidases --- p.11 / Chapter 1.2.3. --- Oxidative Stress and Diseases --- p.11 / Chapter 1.2.4. --- Endometriosis and Oxidative Stress --- p.12 / Chapter 1.2.5. --- Inflammatory Response --- p.13 / Chapter 1.2.6. --- Animal Models of Endometriosis --- p.14 / Chapter 1.3. --- Angiogenesis --- p.15 / Chapter 1.3.1. --- Angiogenesis and Diseases --- p.16 / Chapter 1.3.2. --- Animal Models of Angiogenesis --- p.17 / Chapter 1.3.3. --- Endometriosis and Angiogenesis --- p.18 / Chapter 1.3.4. --- Anti-angiogenesis Therapy --- p.19 / Chapter 1.3.5. --- Rodent Models of Endometriosis --- p.21 / Chapter Chapter 2. --- Objective and Hypothesis --- p.23 / Chapter Chapter 3. --- Methodology / Chapter 3.1. --- Mouse Models of Endometriosis --- p.24 / Chapter 3.1.1. --- Animals --- p.24 / Chapter 3.1.2. --- Ovariectomy --- p.24 / Chapter 3.1.3. --- Transplantation of Endometrium --- p.25 / Chapter 3.1.3.1. --- Donor mice --- p.25 / Chapter 3.1.3.2. --- Recipient mice --- p.25 / Chapter 3.1.4. --- Luciferase ⁺/⁺ transgenic mice --- p.26 / Chapter 3.1.5. --- Macrophage Depletion Model --- p.26 / Chapter 3.1.6. --- 12/15 Lox Transgenic Knockout Mice --- p.26 / Chapter 3.1.6.1. --- 12/15 Lox Knockout to Wildtype --- p.27 / Chapter 3.1.6.2. --- Wildtype to 12/15 Lox Knockout --- p.27 / Chapter 3.1.7. --- HIF-1α Inhibition Model --- p.27 / Chapter 3.2. --- Growth and Development of Endometriotic Lesions --- p.28 / Chapter 3.2.1. --- Termination --- p.28 / Chapter 3.2.2. --- Lesion Size --- p.28 / Chapter 3.2.3. --- In Vivo Non-Invasive Imaging --- p.28 / Chapter 3.2.3.1. --- Luciferase Imaging --- p.28 / Chapter 3.2.3.2. --- Oxidative Stress Imaging --- p.29 / Chapter 3.2.3.3. --- Angiogenesis Imaging --- p.30 / Chapter 3.2.4. --- Histological Evaluation --- p.30 / Chapter 3.2.5. --- Immunostaining --- p.30 / Chapter 3.2.5.1. --- Immunohistochemistry on Oxidative Stress Markers --- p.30 / Chapter 3.2.5.2. --- Immunohistochemistry on Macrophages and Neutrophils --- p.31 / Chapter 3.2.5.2. --- Immunofluorescence on New Vessel Formation --- p.32 / Chapter 3.2.6. --- Terminal Deoxynucleotidyltransferase (TdT)-mediated dUTP End Labeling (TUNEL) Assay --- p.33 / Chapter 3.2.7. --- Quantitative real-time --- p.33 / Chapter 3.2.7.1. --- qPCR on Apoptotic Factors --- p.33 / Chapter 3.2.7.2. --- qPCR on Hypoxic Factors --- p.34 / Chapter 3.2.7.3. --- qPCR on Angiogenic Factors --- p.34 / Chapter 3.2.8. --- 8-Isoprostane --- p.34 / Chapter 3.3. --- Reproductive safety of PX-478 --- p.35 / Chapter 3.4. --- Data Analysis --- p.36 / Chapter Chapter 4. --- Results --- p.37 / Chapter 4.1. --- Endometriosis Growth and Development --- p.37 / Chapter 4.1.1. --- In vivo Non-Invasive Imaging --- p.37 / Chapter 4.1.2. --- Ectopic Endometriotic Lesions --- p.37 / Chapter 4.1.3. --- Histological Examination --- p.37 / Chapter 4.1.4. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.38 / Chapter 4.1.5. --- Real-time PCR --- p.38 / Chapter 4.1.6. --- Oxidative Stress --- p.38 / Chapter 4.1.6.1. --- Non-invasive Imaging (IVIS) --- p.38 / Chapter 4.1.6.2. --- Measurement of 8-isoprostane --- p.39 / Chapter 4.1.6.3. --- Real-time PCR Analysis on Hypoxic Markers --- p.39 / Chapter 4.1.6.4. --- Immunohistochemistry (HIF-1α and VEGF) --- p.40 / Chapter 4.1.7. --- Angiogenesis --- p.40 / Chapter 4.1.7.1. --- Cellvizio Imaging --- p.40 / Chapter 4.1.7.2. --- Real-time PCR Analysis on Hypoxia & Angiogenic Markers --- p.40 / Chapter 4.1.7.3. --- Immunofluorescence --- p.41 / Chapter 4.2. --- Effects of Estrogen on Oxidative Stress and Angiogenesis --- p.41 / Chapter 4.3. --- Macrophage Depletion --- p.43 / Chapter 4.3.1. --- Lesion Growth and Development --- p.43 / Chapter 4.3.1.1. --- In Vivo Non-Invasive Imaging --- p.43 / Chapter 4.3.1.2. --- Ectopic Endometrium Lesions --- p.44 / Chapter 4.3.1.3. --- Histological Examination --- p.44 / Chapter 4.3.1.4. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.44 / Chapter 4.3.1.5. --- Real-time PCR --- p.45 / Chapter 4.3.2. --- Oxidative stress --- p.45 / Chapter 4.3.2.1. --- In Vivo Imaging --- p.45 / Chapter 4.3.2.2. --- 8-isoprostane --- p.45 / Chapter 4.3.2.3. --- Real-time PCR Analysis on Hypoxic Markers --- p.45 / Chapter 4.3.2.4. --- Immunohistochemistry --- p.46 / Chapter 4.3.3. --- Angiogenesis --- p.46 / Chapter 4.3.3.1. --- Real-time PCR analysis on angiogenic markers --- p.46 / Chapter 4.3.3.2. --- Immunofluorescence --- p.47 / Chapter 4.4. --- 12/15 Lox Transgenic Knockout --- p.47 / Chapter 4.4.1. --- Lesion Growth and Development --- p.47 / Chapter 4.4.1.1. --- Ectopic Endometrium Lesions --- p.47 / Chapter 4.4.1.2. --- Histological Examination --- p.48 / Chapter 4.4.1.3. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.48 / Chapter 4.4.1.4. --- Real-time PCR --- p.49 / Chapter 4.4.2. --- Oxidative Stress --- p.50 / Chapter 4.4.2.1. --- 8-isoprostane --- p.50 / Chapter 4.4.2.2. --- Real-time PCR Analysis on Hypoxic Markers --- p.50 / Chapter 4.4.2.3. --- Immunohistochemistry --- p.51 / Chapter 4.4.3. --- Angiogenesis --- p.51 / Chapter 4.4.3.1. --- Real-time PCR Analysis on Angiogenic Markers --- p.51 / Chapter 4.4.3.2. --- Immunofluorescence --- p.53 / Chapter 4.5. --- HIF-1α inhibition --- p.53 / Chapter 4.5.1. --- Lesion Growth and Development --- p.53 / Chapter 4.5.1.1. --- In Vivo Imaging --- p.53 / Chapter 4.5.1.2. --- Ectopic Endometrium Lesions --- p.54 / Chapter 4.5.1.3. --- Histological examination --- p.54 / Chapter 4.5.1.4. --- Immunohistochemistry (Macrophage and Neutrophil) --- p.54 / Chapter 4.5.1.5. --- Real-time PCR --- p.55 / Chapter 4.5.2. --- Oxidative stress --- p.55 / Chapter 4.5.2.1. --- In Vivo Imaging --- p.55 / Chapter 4.5.2.2. --- 8-isoprostane --- p.55 / Chapter 4.5.2.3. --- Real-time PCR Analysis on Hypoxic Markers --- p.55 / Chapter 4.5.2.4. --- Immunohistochemistry --- p.56 / Chapter 4.5.3. --- Angiogenesis --- p.56 / Chapter 4.5.3.1. --- Real-time PCR Analysis on Angiogenic Markers --- p.56 / Chapter 4.5.3.2. --- Immunofluorescence --- p.57 / Chapter 4.5.4. --- Safety Assessment of PX-478 --- p.58 / Chapter Chapter 5. --- Discussion --- p.59 / Chapter 5.1. --- Animal Model and Transplantation Method --- p.59 / Chapter 5.2. --- Oxidative Stress and Its Role in Early Development of Endometriosis --- p.59 / Chapter 5.3. --- Macrophage and Oxidative Stress in Endometriosis --- p.60 / Chapter 5.4. --- Potential Antioxidative Therapy for Endometriosis Treatment --- p.61 / Chapter 5.5. --- Safety --- p.62 / Chapter 5.6. --- Limitation and Further Studies --- p.63 / Chapter Chapter 6. --- Conclusions --- p.65 / Chapter Chapter 7. --- References --- p.66

Les macrophages sont des cellules de l’immunité innée et sont localisés dans la majorité des organes du corps, présentant des fonctions spécifiques dépendant de leur lieu de résidence.Les macrophages d’origine embryonnaire sont la source majeure des macrophages tissulaires et sont capables de se maintenir à long terme dans la plupart des organes adultes.Cependant, il reste certains organes comme le testicule, où l’origine des macrophages n’est pas clairement déterminée. Le testicule est considéré comme un organe immuno-privilégié et a cette nécessité de protéger de tous contacts les spermatozoïdes des cellules immunitaires, qui pourraient induire une auto-immunité.Les macrophages testiculaires (tMφ) contribuent à maintenir ce statut d’organe immuno-privilégié en produisant des cytokines immunosuppressives. Pour ces raisons, les tMφ peuvent être considérés comme des “ gardiens de la fertilité”. Dans les testicules adultes, deux différentes populations de macrophages, nommées interstitielles et péritubulaires, ont été identifiées en se basant sur leurs morphologies et localisations distinctes, mais leur origine et leur mode de développement et de maintenance restent encore inconnus. En combinant des méthodes de traçage cellulaire et la mise au point d’un modèle de transfert adoptif dans des souriceaux, j’ai démontré que les macrophages d’origine embryonnaire contribuaient exclusivement à la population de tMφ interstitielle dès la naissance et que les tMφ péritubulaires proviennent exclusivement de la moelle osseuse. Après avoir caractérisé les tMφ, mes prochaines investigations se porteront sur l’étude des fonctions de chacune de ces deux populations. / Macrophages are innate immune cells residing in most of the organs of the body and ensure proper organ function. Traditionally, it has been known that macrophages can be derived from HSC progenitors in the bone-marrow (BM), but technology using fate-mapping tools has revealed that macrophages can already be generated from embryonic progenitors. Embryo-derived macrophages are a major source of tissue-resident macrophages and can self-maintain during adulthood. The origin of resident macrophages in the testis, however, so far has not been well studied.Importantly, the testis is considered as an immune-privileged organ by protecting the highly immunogenic spermatozoa sequestrated in the seminiferous tubules from the entrance of immune cells. In the adult testis, macrophages participate in the creation of an immune suppressive microenvironment preventing auto-immune attack. Therefore, testicular macrophages tMφ could be considered as the guardians of fertility. Recently,two different macrophage populations have been identified in the adult testis, called interstitial and peritubular, based on their distinct localization and morphology,but their developmental origin and homeostatic maintenance were unknown.Combining the genetic lineage tracing and the neonatal adoptive transfer model, I could demonstrate that the embryo-derived macrophages give rise exclusively to interstitial tMφ. Peritubular tMφ, however, only emerge postnatally from BM-derived progenitors. .My findings provide framework for future investigations into the distinct functions of these two tMφ populations in establishment of immune-privilege as well as the support of spermatogenesis and male hormone production.

Thesis (Ph. D.)--University of Washington, 2001. / Vita. Includes bibliographical references (leaves 73-91).

Thesis (Ph. D.)--West Virginia University, 2007. / Title from document title page. Document formatted into pages; contains x, 212 p. : ill. (some col.). Includes abstract. Includes bibliographical references.