Browsing by Author "McManus, Jeffrey M."

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    Androgen regulation of pulmonary AR, TMPRSS2 and ACE2 with implications for sex-discordant COVID-19 outcomes
    (Nature, 2021-05-27) Baratchian, Mehdi; McManus, Jeffrey M.; Berk, Mike P.; Nakamura, Fumihiko; Mukhopadhyay, Sanjay; Xu, Weiling; Erzurum, Serpil; Drazba, Judy; Peterson, John; Klein, Eric A.; Gaston, Benjamin; Sharifi, Nima; Pediatrics, School of Medicine
    The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide administration. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.
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    Association Between Asthma and Reduced Androgen Receptor Expression in Airways
    (Endocrine Society, 2022-03-21) McManus, Jeffrey M.; Gaston, Benjamin; Zein, Joe; Sharifi, Nima; Pediatrics, School of Medicine
    A growing body of evidence suggests a role for androgens in asthma and asthma control. This includes a sex discordance in disease rates that changes with puberty, experiments in mice showing androgens reduce airway inflammation, and a reported association between airway androgen receptor (AR) expression and disease severity in asthma patients. We set out to determine whether airway AR expression differs between asthma patients and healthy controls. We analyzed data from 8 publicly available data sets with gene expression profiling from airway epithelial cells obtained both from asthma patients and control individuals. We found that airway AR expression was lower in asthma patients than in controls in both sexes, and that having AR expression below the median in the pooled data set was associated with substantially elevated odds of asthma vs having AR expression above the median (odds ratio 4.89; 95% CI, 3.13-7.65, P < .0001). In addition, our results suggest that whereas the association between asthma and AR expression is present in both sexes in most of the age range analyzed, the association may be absent in prepubescent children and postmenopausal women. Our results add to the existing body of evidence suggesting a role for androgens in asthma control.
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    Benefits of Airway Androgen Receptor Expression in Human Asthma
    (American Thoracic Society, 2021) Zein, Joe G.; McManus, Jeffrey M.; Sharifi, Nima; Erzurum, Serpil C.; Marozkina, Nadzeya; Lahm, Timothy; Giddings, Olivia; Davis, Michael D.; DeBoer, Mark D.; Comhair, Suzy A.; Bazeley, Peter; Kim, Hyun Jo; Busse, William; Calhoun, William; Castro, Mario; Chung, Kian Fan; Fahy, John V.; Israel, Elliot; Jarjour, Nizar N.; Levy, Bruce D.; Mauger, David T.; Moore, Wendy C.; Ortega, Victor E.; Peters, Michael; Bleecker, Eugene R.; Meyers, Deborah A.; Zhao, Yi; Wenzel, Sally E.; Gaston, Benjamin; Biostatistics, School of Public Health
    Rationale: Androgens are potentially beneficial in asthma, but AR (androgen receptor) has not been studied in human airways. Objectives: To measure whether AR and its ligands are associated with human asthma outcomes. Methods: We compared the effects of AR expression on lung function, symptom scores, and fractional exhaled nitric oxide (FeNO) in adults enrolled in SARP (Severe Asthma Research Program). The impact of sex and of androgens on asthma outcomes was also evaluated in the SARP with validation studies in the Cleveland Clinic Health System and the NHANES (U.S. National Health and Nutrition Examination Survey).Measurements and Main Results: In SARP (n = 128), AR gene expression from bronchoscopic epithelial brushings was positively associated with both FEV1/FVC ratio (R2 = 0.135, P = 0.0002) and the total Asthma Quality of Life Questionnaire score (R2 = 0.056, P = 0.016) and was negatively associated with FeNO (R2 = 0.178, P = 9.8 × 10-6) and NOS2 (nitric oxide synthase gene) expression (R2 = 0.281, P = 1.2 × 10-10). In SARP (n = 1,659), the Cleveland Clinic Health System (n = 32,527), and the NHANES (n = 2,629), women had more asthma exacerbations and emergency department visits than men. The levels of the AR ligand precursor dehydroepiandrosterone sulfate correlated positively with the FEV1 in both women and men. Conclusions: Higher bronchial AR expression and higher androgen levels are associated with better lung function, fewer symptoms, and a lower FeNO in human asthma. The role of androgens should be considered in asthma management.
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    Sex, androgens and regulation of pulmonary AR, TMPRSS2 and ACE2
    (Cold Spring Harbor Laboratory, 2020-10-14) Baratchian, Mehdi; McManus, Jeffrey M.; Berk, Mike; Nakamura, Fumihiko; Mukhopadhyay, Sanjay; Xu, Weiling; Erzurum, Serpil; Drazba, Judy; Peterson, John; Klein, Eric A.; Gaston, Ben; Sharifi, Nima; Pediatrics, School of Medicine
    The sex discordance in COVID-19 outcomes has been widely recognized, with males generally faring worse than females and a potential link to sex steroids. A plausible mechanism is androgen-induced expression of TMPRSS2 and/or ACE2 in pulmonary tissues that may increase susceptibility or severity in males. This hypothesis is the subject of several clinical trials of anti-androgen therapies around the world. Here, we investigated the sex-associated TMPRSS2 and ACE2 expression in human and mouse lungs and interrogated the possibility of pharmacologic modification of their expression with anti-androgens. We found no evidence for increased TMPRSS2 expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide did not decrease pulmonary TMPRSS2. On the other hand, ACE2 and AR expression was sexually dimorphic and higher in males than females. ACE2 was moderately suppressible with enzalutamide therapy. Our work suggests that sex differences in COVID-19 outcomes attributable to viral entry are independent of TMPRSS2. Modest changes in ACE2 could account for some of the sex discordance.