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Machado Linde, Francisco

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Machado Linde, Francisco
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Universidad de Murcia. Departamento de Cirugía, Pediatría, Obstetriciay Ginecología
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  • Publication
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    Hypothetical roadmap towards endometriosis: prenatal endocrine-disrupting chemical pollutant exposure,anogenital distance,gut-genital microbiota and subclinical infections
    (Oxford University Press, 2020-02-28) García Peñarrubia, María del Pilar; Ruiz Alcaraz, Antonio José; Martínez-Esparza Alvargonzález, María Concepción; Marín Sánchez, Pilar; Machado Linde, Francisco; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
    BACKGROUND Endometriosis is a gynaecological hormone-dependent disorder that is defined by histological lesions generated by the growth of endometrial-like tissue out of the uterus cavity, most commonly engrafted within the peritoneal cavity, although these lesions can also be located in distant organs. Endometriosis affects ~10% of women of reproductive age, frequently producing severe and, sometimes, incapacitating symptoms, including chronic pelvic pain, dysmenorrhea and dyspareunia, among others. Furthermore, endometriosis causes infertility in ~30% of affected women. Despite intense research on the mechanisms involved in the initial development and later progression of endometriosis, many questions remain unanswered and its aetiology remains unknown. Recent studies have demonstrated the critical role played by the relationship between the microbiome and mucosal immunology in preventing sexually transmitted diseases (HIV), infertility and several gynaecologic diseases. OBJECTIVE AND RATIONALE In this review, we sought to respond to the main research question related to the aetiology of endometriosis. We provide a model pointing out several risk factors that could explain the development of endometriosis. The hypothesis arises from bringing together current findings from large distinct areas, linking high prenatal exposure to environmental endocrine-disrupting chemicals with a short anogenital distance, female genital tract contamination with the faecal microbiota and the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. SEARCH METHODS We performed a search of the scientific literature published until 2019 in the PubMed database. The search strategy included the following keywords in various combinations: endometriosis, anogenital distance, chemical pollutants, endocrine-disrupting chemicals, prenatal exposure to endocrine-disrupting chemicals, the microbiome of the female reproductive tract, microbiota and genital tract, bacterial vaginosis, endometritis, oestrogens and microbiota and microbiota–immune system interactions. OUTCOMES On searching the corresponding bibliography, we found frequent associations between environmental endocrine-disrupting chemicals and endometriosis risk. Likewise, recent evidence and hypotheses have suggested the active role of genital subclinical microbial infections in the development and clinical progression of endometriosis. Hence, we can envisage a direct relationship between higher prenatal exposure to oestrogens or estrogenic endocrine-disrupting compounds (phthalates, bisphenols, organochlorine pesticides and others) and a shorter anogenital distance, which could favour frequent postnatal episodes of faecal microbiota contamination of the vulva and vagina, producing cervicovaginal microbiota dysbiosis. This relationship would disrupt local antimicrobial defences, subverting the homeostasis state and inducing a subclinical inflammatory response that could evolve into a sustained immune dysregulation, closing the vicious cycle responsible for the development of endometriosis. WIDER IMPLICATIONS Determining the aetiology of endometriosis is a challenging issue. Posing a new hypothesis on this subject provides the initial tool necessary to design future experimental, clinical and epidemiological research that could allow for a better understanding of the origin of this disease. Furthermore, advances in the understanding of its aetiology would allow the identification of new therapeutics and preventive actions.
  • Publication
    Open Access
    The role of peritoneal macrophages in endometriosis
    (MDPI, 2021-10-06) Martínez-Esparza Alvargonzález, María Concepción; Ruiz Alcaraz, Antonio José; Marín Sánchez, Pilar; Machado Linde, Francisco; García Peñarrubia, María del Pilar; Ramírez Pávez, Tamara Nadira; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
    Endometriosis is an estrogen-dependent gynecological disorder, defined as the growth of endometrial stromal cells and glands at extrauterine sites. Endometriotic lesions are more frequently located into the abdominal cavity, although they can also be implanted in distant places. Among its etiological factors, the presence of immune dysregulation occupies a prominent place, pointing out the beneficial and harmful outcomes of macrophages in the pathogenesis of this disease. Macrophages are tissue-resident cells that connect innate and adaptive immunity, playing a key role in maintaining local homeostasis in healthy conditions and being critical in the development and sustainment of many inflammatory diseases. Macrophages accumulate in the peritoneal cavity of women with endometriosis, but their ability to clear migrated endometrial fragments seems to be inefficient. Hence, the characteristics of the peritoneal immune system in endometriosis must be further studied to facilitate the search for new diagnostic and therapeutic tools. In this review, we summarize recent relevant advances obtained in both mouse, as the main animal model used to study endometriosis, and human, focusing on peritoneal macrophages obtained from endometriotic patients and healthy donors, under the perspective of its future clinical translation to the role that these cells play on this pathology.
  • Publication
    Open Access
    Systemic immune and tumor marker profiles in ovarian and deep infiltrating endometriosis: associations with disease severity and symptom burden
    (MDPI, 2025-10-01) Marín Sánchez, Pilar; Nebot, Ana; García-Izquierdo, Laura; Nieto-Meca, Lucía; Sánchez, Rocío; Machado Linde, Francisco; Martínez-Esparza Alvargonzález, María Concepción; Ramírez Pávez, Tamara Nadira; Bioquímica y Biología Molecular B e Inmunología; Facultad de Medicina
    Endometriosis is a chronic, estrogen-dependent inflammatory disease with heterogeneous clinical manifestations and uncertain systemic immune involvement. This study aimed to characterize peripheral immune profiles and circulating tumor markers in women with ovarian endometrioma (OE) and deep infiltrating endometriosis (DIE), and to explore their associations with disease severity, symptom burden, and physical health perception. Peripheral blood leukocyte subsets, plasma cytokines, and tumor markers (CA125, CA19-9, CEA, HE4) were analyzed in 146 patients and 50 healthy controls. OE was associated with increased monocyte counts and reduced neutrophil proportions, while DIE showed elevated levels of IL-8 and Galectin-1. IL-33 levels correlated negatively with the revised American Society for Reproductive Medicine (rASRM) scores and positively with neutrophil proportion, suggesting a role in systemic immune regulation. Tumor marker levels varied by subtype: CA19-9 was higher in OE, and CEA in DIE. CA125 correlated with disease severity, and CEA with monocyte levels. Exploratory heatmaps revealed consistent immune-tumor associations linked to anatomical severity and symptom profiles. Although exploratory, these findings highlight the presence of distinct systemic immune patterns in endometriosis and support the potential of integrative blood-based biomarkers for future diagnostic and stratification strategies.
  • Publication
    Restricted
    Isolation of functional mature peritoneal macrophages from healthy humans
    (Wiley, 2019-11-11) Ruiz Alcaraz, Antonio José; Martınez-Banaclocha, Helios; Marín Sánchez, Pilar; Carmona-Martínez Violeta; Iniesta-Albadalejo, Miguel Angel; Tristan-Manzano, María; García Peñarrubia, María del Pilar; Machado Linde, Francisco; Pelegrín Vivancos, Pablo; Martínez-Esparza Alvargonzález, María Concepción; Tapia Abellán, Ana; Bioquímica y Biología Molecular B e Inmunología; Facultad de Biología
    Macrophages play an important role in the inflammatory response. Their various biological functions are induced by different membrane receptors, including Toll-like receptors, which trigger several intracellular signaling cascades and activate the inflammasomes, which in turn elicit the release of inflammatory mediators such as cytokines. In this study, we present a novel method for the isolation of human mature peritoneal macrophages. This method can be easily implemented by gynecologists who routinely perform laparoscopy for sterilization by tubal ligation or surgically intervene in benign gynecological pathologies. Our method confirms that macrophages are the main peritoneal leukocyte subpopulation isolated from the human peritoneum in homeostasis. We showed that primary human peritoneal macrophages present phagocytic and oxidative activities, and respond to activation of the main proinflammatory pathways such as Toll-like receptors and inflammasomes, resulting in the secretion of different proinflammatory cytokines. Therefore, this method provides a useful tool for characterizing primary human macrophages as control cells for studies of molecular inflammatory pathways in steady-state conditions and for comparing them with those obtained from pathologies involving the peritoneal cavity. Furthermore, it will facilitate advances in the screening of anti-inflammatory compounds in the human system.