Browsing by Author "Krishnan, Sheila"

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    A case report of hepatopulmonary syndrome in hereditary hemorrhagic telangiectasia (HHT): Not all right-to-left shunting in HHT is due to pulmonary arteriovenous malformations
    (Wolters Kluwer, 2018-08) Krishnan, Sheila; Lahm, Tim; Medicine, School of Medicine
    RATIONALE: Hereditary hemorrhagic telangiectasia (HHT) is an autosomal dominant disorder characterized by abnormal vessel growth that results in telangiectasias and arteriovenous malformations (AVMs) in the skin, mucosa, and viscera. Up to 30% of patients with HHT exhibit pulmonary AVMs (PAVMs), clinically manifesting as right-to-left shunting and hypoxemia. PATIENT CONCERNS: We report an unusual and novel case of a patient with HHT who lacked clinical sequelae of portal hypertension but presented to clinic with hypoxemia without dyspnea. DIAGNOSES: Diagnostic workup revealed noncardiac right-to-left shunting due to hepatopulmonary syndrome (HPS) from HHT-induced portal hypertension rather than PAVMs. The diagnosis was confirmed by the absence of PAVMs on chest computed tomography and evidence of elevated portal pressures as noted by the presence of small esophageal varices on upper endoscopy and histologic findings on liver biopsy. INTERVENTION: Due to the patient's mild symptoms, no further intervention was required. He was closely followed up in the outpatient setting for changes in symptoms and underwent annual screening for development of PAVMs. OUTCOMES: The patient continues to do well clinically. He has not experienced worsening hypoxemia or dyspnea and has not developed PAVMs. LESSONS: Given that management of hypoxemia in HPS drastically differs from that of hypoxemia due to PAVMs, this case demonstrates the importance of evaluating HHT patients for HPS if they exhibit impaired oxygenation and noncardiac right-to-leftshunting in the setting of hepatic arteriovenous shunting.
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    Management of broncholithiasis
    (AME Publishing Company, 2018-10) Krishnan, Sheila; Kniese, Christopher M.; Mankins, Mark; Heitkamp, Darel E.; Sheski, Francis D.; Kesler, Kenneth A.; Medicine, School of Medicine
    Broncholithiasis is a condition in which calcified material has entered the tracheobronchial tree, at times causing airway obstruction and inflammation. Broncholiths generally originate as calcified material in mediastinal lymph nodes that subsequently erode into adjacent airways, often as a result of prior granulomatous infection. Disease manifestations range from asymptomatic stones in the airway to life-threatening complications, including massive hemoptysis and post-obstructive pneumonia. Radiographic imaging, particularly computed tomography scanning of the chest, is integral in the evaluation of suspected broncholithiasis and can be helpful to assess involvement of adjacent structures, including vasculature, prior to any planned intervention. Management strategies largely depend on the severity of disease. Observation is warranted in asymptomatic cases, while therapeutic bronchoscopy and surgical interventions may be necessary for cases involving complications. Bronchoscopic extraction is often feasible in cases in which the broncholith is freely mobile within the airway, whereas partially-embedded broncholiths represent additional challenges. Surgical intervention is indicated for advanced cases deemed not amenable to endoscopic management. Complex cases involving complications such as massive hemoptysis and/or bronchomediastinal fistula formation are best managed with a multidisciplinary approach, utilizing expertise from fields such as pulmonology, radiology, and thoracic surgery.
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    Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure
    (Federation of American Societies for Experimental Biology, 2018-04) Mizumura, Kenji; Justice, Matthew J.; Schweitzer, Kelly S.; Krishnan, Sheila; Bronova, Irina; Berdyshev, Evgeny V.; Hubbard, Walter C.; Pewzner-Jung, Yael; Futerman, Anthony H.; Choi, Augustine M. K.; Petrache, Irina; Medicine, School of Medicine
    The mechanisms by which lung structural cells survive toxic exposures to cigarette smoke (CS) are not well defined but may involve proper disposal of damaged mitochondria by macro-autophagy (mitophagy), processes that may be influenced by pro-apoptotic ceramide (Cer) or its precursor dihydroceramide (DHC). Human lung epithelial and endothelial cells exposed to CS exhibited mitochondrial damage, signaled by phosphatase and tensin homolog-induced putative kinase 1 (PINK1) phosphorylation, autophagy, and necroptosis. Although cells responded to CS by rapid inhibition of DHC desaturase, which elevated DHC levels, palmitoyl (C16)-Cer also increased in CS-exposed cells. Whereas DHC augmentation triggered autophagy without cell death, the exogenous administration of C16-Cer was sufficient to trigger necroptosis. Inhibition of Cer-generating acid sphingomyelinase reduced both CS-induced PINK1 phosphorylation and necroptosis. When exposed to CS, Pink1-deficient ( Pink1-/-) mice, which are protected from airspace enlargement compared with wild-type littermates, had blunted C16-Cer elevations and less lung necroptosis. CS-exposed Pink1-/- mice also exhibited significantly increased levels of lignoceroyl (C24)-DHC, along with increased expression of Cer synthase 2 ( CerS2), the enzyme responsible for its production. This suggested that a combination of high C24-DHC and low C16-Cer levels might protect against CS-induced necroptosis. Indeed, CerS2-/- mice, which lack C24-DHC at the expense of increased C16-Cer, were more susceptible to CS, developing airspace enlargement following only 1 month of exposure. These results implicate DHCs, in particular, C24-DHC, as protective against CS toxicity by enhancing autophagy, whereas C16-Cer accumulation contributes to mitochondrial damage and PINK1-mediated necroptosis, which may be amplified by the inhibition of C24-DHC-producing CerS2.-Mizumura, K., Justice, M. J., Schweitzer, K. S., Krishnan, S., Bronova, I., Berdyshev, E. V., Hubbard, W. C., Pewzner-Jung, Y., Futerman, A. H., Choi, A. M. K., Petrache, I. Sphingolipid regulation of lung epithelial cell mitophagy and necroptosis during cigarette smoke exposure.
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    Transcriptomic modifications in developmental cardiopulmonary adaptations to chronic hypoxia using a murine model of simulated high-altitude exposure
    (American Physiological Society, 2020-09-01) Krishnan, Sheila; Stearman, Robert S.; Zeng, Lily; Fisher, Amanda; Mickler, Elizabeth A.; Rodriguez, Brooke H.; Simpson, Edward R.; Cook, Todd; Slaven, James E.; Ivan, Mircea; Geraci, Mark W.; Lahm, Tim; Tepper, Robert S.; Medicine, School of Medicine
    Mechanisms driving adaptive developmental responses to chronic high-altitude (HA) exposure are incompletely known. We developed a novel rat model mimicking the human condition of cardiopulmonary adaptation to HA starting at conception and spanning the in utero and postnatal timeframe. We assessed lung growth and cardiopulmonary structure and function and performed transcriptome analyses to identify mechanisms facilitating developmental adaptations to chronic hypoxia. To generate the model, breeding pairs of Sprague-Dawley rats were exposed to hypobaric hypoxia (equivalent to 9,000 ft elevation). Mating, pregnancy, and delivery occurred in hypoxic conditions. Six weeks postpartum, structural and functional data were collected in the offspring. RNA-Seq was performed on right ventricle (RV) and lung tissue. Age-matched breeding pairs and offspring under room air (RA) conditions served as controls. Hypoxic rats exhibited significantly lower body weights and higher hematocrit levels, alveolar volumes, pulmonary diffusion capacities, RV mass, and RV systolic pressure, as well as increased pulmonary artery remodeling. RNA-Seq analyses revealed multiple differentially expressed genes in lungs and RVs from hypoxic rats. Although there was considerable similarity between hypoxic lungs and RVs compared with RA controls, several upstream regulators unique to lung or RV were identified. We noted a pattern of immune downregulation and regulation patterns of immune and hormonal mediators similar to the genome from patients with pulmonary arterial hypertension. In summary, we developed a novel murine model of chronic hypoxia exposure that demonstrates functional and structural phenotypes similar to human adaptation. We identified transcriptomic alterations that suggest potential mechanisms for adaptation to chronic HA.