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This Month in AJP

    Open ArchivePublished:November 21, 2019DOI:https://doi.org/10.1016/j.ajpath.2019.11.001

        Managing Pulmonary Hypertension

        The role of Kv11.1 potassium channels in the lung is unclear. Shults et al (Am J Pathol 2020, 48–56) studied the expression of Kv11.1 in healthy human and rat lung tissues and in humans with chronic obstructive pulmonary disease (COPD)-associated pulmonary hypertension (PH) and rats with pulmonary arterial hypertension (PAH). Kv11.1 channels are amply expressed in and confined to the large pulmonary arteries (PAs) of healthy lung tissues. This expression increases in human lungs affected by COPD-associated PH and in mouse lungs with PAH, with detectable expression in small PAs. The Kv11.1 channel expression in small PAs follows the time course of pulmonary vascular remodeling in PAH in rats. Blocking Kv11.1 channel in PAH rats inhibited PAH-associated pulmonary vascular remodeling. Kv11.1 channels may be therapeutically targeted in PH treatment.

        Suppressing Dry Eye Disease

        Despite implications in dry eye disease (DED), the role of the neuropeptide substance P (SP) in its pathogenesis is unclear. Using cultured cells and a mouse model of DED, Yu et al (Am J Pathol 2020, 125–133) studied this role. SP is constitutively expressed at the ocular surface. SP, primarily produced from the trigeminal ganglion neurons in DED, augments the maturation of bone-marrow–derived dendritic cells in vitro. Antagonizing SP signaling abrogates this effect in vitro and in vivo. Blocking SP signaling may suppress ocular surface disease.

        Dissecting Endometriotic Fibrosis

        Myocardial infarction studies revealed that transcription factor 21 (TCF21) is an upstream regulatory gene of periostin. Ganieva et al (Am J Pathol 2020, 145–157) studied the role of TCF21 and periostin in the development of endometriosis. Archived tissue sections from normal endometrium and various samples from endometriosis lesions were studied. TCF21 regulates the expression of periostin, and both periostin and TCF21 are up-regulated in endometriosis lesions, especially in samples from women with deep endometriosis. TCF21 may serve as a biomarker and a therapeutic target in endometriosis management.

        Delaying Nephronophthisis Type 7

        Mutations in GLIS2, which encodes a nuclear transcription factor, cause nephronophthisis (NPHP) type 7. By genetically altering Glis2 alone and in combination with components of the DNA-damage response pathway in mice, Jin et al (Am J Pathol 2020, 176–189) examined the underlying mechanisms. Suppressing Glis2 activates toll-like receptor 2/interleukin receptor 1 (TLR2/IL-1R) signaling. A combined loss of Glis2 and TLR2 activity improves the regenerative potential of tubular cells. Inhibition of TLR2/IL-1R signaling in conjunction with senolytic therapy may delay NPHP type 7 progression.

        Understanding Fibroblast Plasticity

        The myofibroblast-like cancer-associated fibroblasts (CAFs) are critical to the growth and metastasis of cancer. Using mouse melanoma tumor and spheroid tissue culture models, Tsang et al (Am J Pathol 2020, 206–221) studied the underlying mechanisms. As anticipated, the stem cell transcription factor Sox2 is induced in stromal CAFs derived from Col1a2-expressing fibroblasts. The differentiation of skin progenitor cells into myofibroblast is CCN2-dependent. CCN2 may be therapeutically targeted to modulate fibroblast plasticity and manage melanoma.

        Linked Article

        • Innate Immune Signaling Contributes to Tubular Cell Senescence in the Glis2 Knockout Mouse Model of Nephronophthisis
          The American Journal of PathologyVol. 190Issue 1
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            Nephronophthisis (NPHP), the leading genetic cause of end-stage renal failure in children and young adults, is a group of autosomal recessive diseases characterized by kidney-cyst degeneration and fibrosis for which no therapy is currently available. To date, mutations in >25 genes have been identified as causes of this disease that, in several cases, result in chronic DNA damage in kidney tubular cells. Among such mutations, those in the transcription factor–encoding GLIS2 cause NPHP type 7. Loss of function of mouse Glis2 causes senescence of kidney tubular cells.
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        • Increased Smooth Muscle Kv11.1 Channel Expression in Pulmonary Hypertension and Protective Role of Kv11.1 Channel Blocker Dofetilide
          The American Journal of PathologyVol. 190Issue 1
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            Kv11.1 potassium channels are essential for heart repolarization. Prescription medication that blocks Kv11.1 channels lengthens the ventricular action potential and causes cardiac arrhythmias. Surprisingly little is known about the Kv11.1 channel expression and function in the lung tissue. Here we report that Kv11.1 channels were abundantly expressed in the large pulmonary arteries (PAs) of healthy lung tissues from humans and rats. Kv11.1 channel expression was increased in the lungs of humans affected by chronic obstructive pulmonary disease–associated pulmonary hypertension and in the lungs of rats with pulmonary arterial hypertension (PAH).
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        • Insights into Fibroblast Plasticity: Cellular Communication Network 2 Is Required for Activation of Cancer-Associated Fibroblasts in a Murine Model of Melanoma
          The American Journal of PathologyVol. 190Issue 1
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            Tumor stroma resembles a fibrotic microenvironment, being characterized by the presence of myofibroblast-like cancer-associated fibroblasts (CAFs). In wild-type mice injected with melanoma cells, we show that the stem cell transcription factor Sox2 is expressed by tumor cells and induced in CAFs derived from synthetic fibroblasts. These fibroblasts were labeled postnatally with green fluorescent protein using mice expressing a tamoxifen-dependent Cre recombinase under the control of a fibroblast-specific promoter/enhancer.
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        • Neurokinin-1 Receptor Antagonism Ameliorates Dry Eye Disease by Inhibiting Antigen-Presenting Cell Maturation and T Helper 17 Cell Activation
          The American Journal of PathologyVol. 190Issue 1
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            Neuroinflammation plays an important role in the pathogenesis of ocular surface disease, including dry eye disease (DED), but little is known about the contribution of substance P (SP) to DED. In this study, we investigated the expression of SP at the ocular surface and evaluated its effect on maturation of antigen-presenting cells (APCs), the key cell component involved in the induction of type 17 helper T-cell (Th17) response in DED. The effect of topical blockade of SP signaling was further investigated using neurokinin-1 receptor (NK1R) inhibitors on APC maturation, Th17 cell activation, and disease severity in a mouse model of DED.
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        • Involvement of Transcription Factor 21 in the Pathogenesis of Fibrosis in Endometriosis
          The American Journal of PathologyVol. 190Issue 1
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            Repeated tissue injury and repair and fibrosis play a pivotal role in endometriosis. Fibrotic tissue consists of extracellular matrix proteins, regulated by transcriptional factors promoting cell proliferation and survival. Periostin is one of the putative key extracellular matrix proteins. This study aimed to determine whether transcription factor 21 (TCF21) is involved in the development of endometriosis as an upstream regulatory gene of periostin. Formalin-fixed, paraffin-embedded tissue samples [normal endometrium of women without endometriosis; eutopic endometrium of women with endometriosis; ovarian endometriosis (OE); and deep infiltrating endometriosis (DIE)] and respective cells were analyzed.
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