Browsing by Author "Erzurum, Serpil"
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Item 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 MedicineThe 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.Item CCL5 is a Potential Bridge Between Type-1 and Type-2 Inflammation in Asthma(Elsevier, 2023) Gauthier, Marc; Kale, Sagar Laxman; Oriss, Timothy B.; Gorry, Michael; Ramonell, Richard P.; Dalton, Kathryn; Ray, Prabir; Fahy, John V.; Seibold, Max A.; Castro, Mario; Jarjour, Nizar; Gaston, Benjamin; Bleecker, Eugene R.; Meyers, Deborah A.; Moore, Wendy; Hastie, Annette T.; Israel, Elliot; Levy, Bruce D.; Mauger, David; Erzurum, Serpil; Comhair, Suzy A.; Wenzel, Sally E.; Ray, Anuradha; Pediatrics, School of MedicineBackground: Type 1 (T1) inflammation (marked by IFN-γ expression) is now consistently identified in subsets of asthma cohorts, but how it contributes to disease remains unclear. Objective: We sought to understand the role of CCL5 in asthmatic T1 inflammation and how it interacts with both T1 and type 2 (T2) inflammation. Methods: CCL5, CXCL9, and CXCL10 messenger RNA expression from sputum bulk RNA sequencing, as well as clinical and inflammatory data were obtained from the Severe Asthma Research Program III (SARP III). CCL5 and IFNG expression from bronchoalveolar lavage cell bulk RNA sequencing was obtained from the Immune Mechanisms in Severe Asthma (IMSA) cohort and expression related to previously identified immune cell profiles. The role of CCL5 in tissue-resident memory T-cell (TRM) reactivation was evaluated in a T1high murine severe asthma model. Results: Sputum CCL5 expression strongly correlated with T1 chemokines (P < .001 for CXCL9 and CXCL10), consistent with a role in T1 inflammation. CCL5high participants had greater fractional exhaled nitric oxide (P = .009), blood eosinophils (P < .001), and sputum eosinophils (P = .001) in addition to sputum neutrophils (P = .001). Increased CCL5 bronchoalveolar lavage expression was unique to a previously described T1high/T2variable/lymphocytic patient group in the IMSA cohort, with IFNG trending with worsening lung obstruction only in this group (P = .083). In a murine model, high expression of the CCL5 receptor CCR5 was observed in TRMs and was consistent with a T1 signature. A role for CCL5 in TRM activation was supported by the ability of the CCR5 inhibitor maraviroc to blunt reactivation. Conclusion: CCL5 appears to contribute to TRM-related T1 neutrophilic inflammation in asthma while paradoxically also correlating with T2 inflammation and with sputum eosinophilia.Item No evidence that androgen regulation of pulmonary TMPRSS2 explains sex-discordant COVID-19 outcomes(2020-03-21) Baratchian, Mehdi; McManus, Jeffrey; Berk, Mike; Nakamura, Fumihiko; Erzurum, Serpil; Mukhopadhyay, Sanjay; Drazba, Judy; Peterson, John; Gaston, Ben; Sharifi, Nima; Pediatrics, School of MedicineAbstract
The recent emergence of SARS-CoV-2 and the subsequent COVID-19 pandemic have posed a public health crisis. Higher morbidity and mortality of men with COVID-19 may be explained by androgen-driven mechanisms. One such proposed mechanism is androgen regulation of pulmonary TMPRSS2, the host co-receptor for SARS-CoV-2. We find no evidence for increased TMPRSS2 mRNA expression in the lungs of males compared to females in humans or mice. Furthermore, in male mice, treatment with the androgen receptor antagonist enzalutamide does not decrease pulmonary TMPRSS2 expression. Nevertheless, regardless of sex, smoking significantly increases the expression of TMPRSS2, which reverts back to never-smoker levels in former smokers. Finally, we show that in mouse models, despite equivalent AR transcript levels, males express markedly higher amounts of AR protein. If a similar sex-specific regulation of AR protein occurs in human lung, androgens could play important roles in clinical outcome of COVID-19 through mechanisms other than TMPRSS2 regulation.
Item 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 MedicineThe 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.