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This Month in AJP

    Open ArchivePublished:December 17, 2019DOI:https://doi.org/10.1016/j.ajpath.2019.12.001

        Modeling Inflammatory Preterm Birth

        Over twenty-five percent of preterm births (PTBs) result from inflammation or infection. Zierden et al (Am J Pathol 2020, 295–306) generated a new mouse model of inflammation-related PTB. The common lipopolysaccharide (LPS)-preterm birth model that used a single proximal uterine injection (SPI) was improved with a novel double distal injection (DDI). The total LPS dose was divided into two injections given distally into each uterine horn. Compared to the SPI method, the DDI method enhanced uterine fluid distribution and PTB induction rates at a specific LPS dose, and increased the expression of genes related to myometrial contractility more significantly. The DDI mouse model may help test potential therapeutics against inflammation-induced PTB.

        Diagnosing Rickettsial Infection

        Mediterranean spotted fever results in high mortality due to a lack of availability of diagnostic tests. Using quantitative proteomics, Zhao et al (Am J Pathol 2020, 307–322) analyzed the proteins expressed during Rickettsia infection to identify potential biomarkers. Analysis of secreted proteins from primary human umbilical vein endothelial cells infected with Rickettsia conorii, and proteins present in the plasma and serum derived from mice and humans infected with R. conorii independently identified one rickettsial putative amidase, RC0497, to be differentially expressed. RC0497 may serve as a biomarker for diagnosing Rickettsial infection.

        Targeting Urothelial Carcinoma in Situ

        There is an urgent need for effective bladder-preserving therapies for the treatment of urothelial carcinoma in situ (CIS). Using laser-capture microdissection and small exome sequencing panel, Garczyk et al (Am J Pathol 2020, 323–332) identified therapeutically actionable genomic alterations (GAs) in a cohort of fresh-frozen CIS. The majority of CIS cases displayed at least one potentially actionable GA. These findings may help guide mechanistic studies of urothelial CIS pathogenesis in the future.

        Preventing Liver Damage during Regeneration

        Liver sinusoidal endothelial cells (LSECs) express hepatocyte growth factor (Hgf), which is critical for prenatal development, metabolic homeostasis, and liver regeneration. Zhang and et al (Am J Pathol 2020, 358–371) studied the role of LSEC-derived Hgf in physiologic homeostasis and liver regeneration. Hgf was deleted in mouse LSECs (LSEC-KO) during embryonic phase. Though the liver developed normally, liver regeneration was compromised after partial hepatectomy in LSEC-KO mice. LSEC-derived Hgf may prevent liver damage during regeneration.

        Collagen VI Helps Maintain Lung Structure

        Despite its widespread presence, the role of collagen VI (COL6) in the lung is unclear. Using established Col6a1−/− mice, Mereness et al (Am J Pathol 2020, 426–441) studied lung morphology. Col6a1−/− mice exhibited altered airway architecture and physiology as well as abnormal behavior of airway epithelial cells. Decreased COL6 expression may impact development or homeostasis, contributing to chronic lung disease.

        Linked Article

        • Collagen VI Deficiency Results in Structural Abnormalities in the Mouse Lung
          The American Journal of PathologyVol. 190Issue 2
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            Collagen VI (COL6) is known for its role in a spectrum of congenital muscular dystrophies, which are often accompanied by respiratory dysfunction. However, little is known regarding the function of COL6 in the lung. We confirmed the presence of COL6 throughout the basement membrane region of mouse lung tissue. Lung structure and organization were studied in a previously described Col6a1−/− mouse, which does not produce detectable COL6 in the lung. The Col6a1−/− mouse displayed histopathologic alveolar and airway abnormalities.
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        • Next-Generation Sequencing Reveals Potential Predictive Biomarkers and Targets of Therapy for Urothelial Carcinoma in Situ of the Urinary Bladder
          The American Journal of PathologyVol. 190Issue 2
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            Bacillus Calmette-Guérin instillation after removal of the tumor is the first line of treatment for urothelial carcinoma in situ (CIS), the precursor lesion of most muscle-invasive bladder cancers. Bacillus Calmette-Guérin therapy fails in >50% of cases, and second-line radical cystectomy is associated with overtreatment and drastic lifestyle consequences. Given the need for alternative bladder-preserving therapies, we identified genomic alterations (GAs) in urothelial CIS having the potential to predict response to targeted therapies.
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        • Angiocrine Hepatocyte Growth Factor Signaling Controls Physiological Organ and Body Size and Dynamic Hepatocyte Proliferation to Prevent Liver Damage during Regeneration
          The American Journal of PathologyVol. 190Issue 2
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            Liver sinusoidal endothelial cells (LSECs) control organ functions, metabolism, and development through the secretion of angiokines. LSECs express hepatocyte growth factor (Hgf), which is involved in prenatal development, metabolic homeostasis, and liver regeneration. This study aimed to elucidate the precise contribution of LSEC-derived Hgf in physiological homeostasis and liver regeneration. Stab2-iCretg/wt;Hgffl/fl (HgfΔLSEC) mice were generated to abrogate Hgf expression selectively in LSECs from early fetal development onwards, to study global development, metabolic and endothelial zonation, and organ functions as well as liver regeneration in response to 70% partial hepatectomy (PH).
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        • Characterization of an Adapted Murine Model of Intrauterine Inflammation–Induced Preterm Birth
          The American Journal of PathologyVol. 190Issue 2
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            Preterm birth (PTB) affects nearly 15 million infants each year. Of these PTBs, >25% are a result of inflammation or infection. Animal models have improved our understanding of the mechanisms leading to PTB. Prior work has described induction of intrauterine inflammation in mice with a single injection of lipopolysaccharide (LPS). Herein, we have improved the reproducibility and potency of LPS in the model using two injections distal to the cervix. An in vivo imaging system revealed more uniform distribution of Evans Blue Dye using a double distal injection (DDI) approach compared with a single proximal injection (SPI).
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        • Quantitative Proteomics of the Endothelial Secretome Identifies RC0497 as Diagnostic of Acute Rickettsial Spotted Fever Infections
          The American Journal of PathologyVol. 190Issue 2
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            Mediterranean spotted fever is a reemerging acute tick-borne infection produced by the α-proteobacterium, Rickettsia conorii. Rickettsia conorii infects vascular endothelial cells producing disseminated plasma leakage, manifesting as nonspecific fever, headache, and maculopapular rash. Because there are no available tests of early infection, Mediterranean spotted fever is often undiagnosed and untreated, resulting in significant mortality. To address this critical need, we have applied a quantitative proteomics pipeline for analyzing the secretome of primary human umbilical vein endothelial cells.
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          Open Archive