Endogenous inhibitory mechanisms in asthma

Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E2, prostaglandin I2, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma. Endogenous inhibitory mechanisms promote resolution of inflammation, enhance tissue repair and integrity, and promote homeostasis in the lung. These mechanisms include steroid hormones, regulatory T cells, IL-10, prostaglandin E2, prostaglandin I2, lipoxins, resolvins, protectins, maresins, glucagon-like peptide-1 receptor, adrenomedullin, nitric oxide, and carbon monoxide. Here we review the most recent literature regarding these endogenous inhibitory mechanisms in asthma, which remain a promising target for the prevention and treatment of asthma. Since the publication of a review summarizing the known endogenous inhibitory mechanisms in asthma more than 20 years ago,1Barnes P.J. Endogenous inhibitory mechanisms in asthma.Am J Respir Crit Care Med. 2000; 161: S176-S181Crossref PubMed Google Scholar our understanding of these pathways has deepened significantly. Here we present an updated review of the endogenous inhibitory mechanisms that orchestrate the resolution of inflammation and tissue repair in asthma (Table I).2Barnes P.J. Glucocorticosteroids: current and future directions.Br J Pharmacol. 2011; 163: 29-43Crossref PubMed Scopus (396) Google Scholar, 3Schleimer R.P. Potential regulation of inflammation in the lung by local metabolism of hydrocortisone.Am J Respir Cell Mol Biol. 1991; 4: 166-173Crossref PubMed Google Scholar, 4Blum A. Maser E. Enzymology and molecular biology of glucocorticoid metabolism in humans.Prog Nucleic Acid Res Mol Biol. 2003; 75: 173-216Crossref PubMed Scopus (21) Google Scholar, 5Tomlinson J.W. Walker E.A. Bujalska I.J. Draper N. Lavery G.G. Cooper M.S. et al.11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (859) Google Scholar, 6Hu A. Fatma S. Cao J. Grunstein J.S. Nino G. Grumbach Y. et al.Th2 cytokine-induced upregulation of 11beta-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L790-L803Crossref PubMed Scopus (0) Google Scholar, 7Josephson M.B. Jiao J. Xu S. Hu A. Paranjape C. Grunstein J.S. et al.IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response.Am J Physiol Lung Cell Mol Physiol. 2012; 303: L382-L390Crossref PubMed Scopus (13) Google Scholar, 8Zhang T.Y. Ding X. Daynes R.A. The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities.J Immunol. 2005; 174: 879-889Crossref PubMed Google Scholar, 9Bulkhi A.A. Shepard 2nd, K.V. Casale T.B. Cardet J.C. Elevated testosterone is associated with decreased likelihood of current asthma regardless of sex.J Allergy Clin Immunol Pract. 2020; 8 (35.e4): 3029Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10Mohan S.S. Knuiman M.W. Divitini M.L. James A.L. Musk A.W. Handelsman D.J. et al.Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.Clin Endocrinol (Oxf). 2015; 83: 268-276Crossref PubMed Scopus (48) Google Scholar, 11Svartberg J. Schirmer H. Medbo A. Melbye H. Aasebo U. Reduced pulmonary function is associated with lower levels of endogenous total and free testosterone. The Tromso study.Eur J Epidemiol. 2007; 22: 107-112Crossref PubMed Scopus (0) Google Scholar, 12Wenzel S.E. Robinson C.B. Leonard J.M. Panettieri Jr., R.A. Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo-controlled study.Allergy Asthma Proc. 2010; 31: 461-471Crossref PubMed Scopus (51) Google Scholar, 13Cephus J.Y. Stier M.T. Fuseini H. Yung J.A. Toki S. Bloodworth M.H. et al.Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation.Cell Rep. 2017; 21: 2487-2499Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 14Espinoza J. Montano L.M. Perusquia M. Nongenomic bronchodilating action elicited by dehydroepiandrosterone (DHEA) in a guinea pig asthma model.J Steroid Biochem Mol Biol. 2013; 138: 174-182Crossref PubMed Scopus (21) Google Scholar Impairment of endogenous inhibitory mechanisms may amplify the underlying inflammation in asthma, thus increasing disease severity. Understanding endogenous inhibitory mechanisms may also identify novel targets for therapy.Table IEndogenous inhibitory mechanisms in asthmaEndogenous inhibitory mechanismCellular sourcesMediator-specific effectsSteroid hormones•Adrenal glands and gonads•Endogenous glucocorticoids have broad anti-inflammatory effects, mainly by binding intracellular receptors and modulating gene transcription2Barnes P.J. Glucocorticosteroids: current and future directions.Br J Pharmacol. 2011; 163: 29-43Crossref PubMed Scopus (396) Google Scholar•11β-HSD1 and 11β-HSD2 regulate local levels of endogenous glucocorticoids3Schleimer R.P. Potential regulation of inflammation in the lung by local metabolism of hydrocortisone.Am J Respir Cell Mol Biol. 1991; 4: 166-173Crossref PubMed Google Scholar, 4Blum A. Maser E. Enzymology and molecular biology of glucocorticoid metabolism in humans.Prog Nucleic Acid Res Mol Biol. 2003; 75: 173-216Crossref PubMed Scopus (21) Google Scholar, 5Tomlinson J.W. Walker E.A. Bujalska I.J. Draper N. Lavery G.G. Cooper M.S. et al.11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (859) Google Scholar, 6Hu A. Fatma S. Cao J. Grunstein J.S. Nino G. Grumbach Y. et al.Th2 cytokine-induced upregulation of 11beta-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L790-L803Crossref PubMed Scopus (0) Google Scholar, 7Josephson M.B. Jiao J. Xu S. Hu A. Paranjape C. Grunstein J.S. et al.IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response.Am J Physiol Lung Cell Mol Physiol. 2012; 303: L382-L390Crossref PubMed Scopus (13) Google Scholar, 8Zhang T.Y. Ding X. Daynes R.A. The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities.J Immunol. 2005; 174: 879-889Crossref PubMed Google Scholar•Testosterone decreases the number of ILC22s and inhibits airway inflammation9Bulkhi A.A. Shepard 2nd, K.V. Casale T.B. Cardet J.C. Elevated testosterone is associated with decreased likelihood of current asthma regardless of sex.J Allergy Clin Immunol Pract. 2020; 8 (35.e4): 3029Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10Mohan S.S. Knuiman M.W. Divitini M.L. James A.L. Musk A.W. Handelsman D.J. et al.Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.Clin Endocrinol (Oxf). 2015; 83: 268-276Crossref PubMed Scopus (48) Google Scholar, 11Svartberg J. Schirmer H. Medbo A. Melbye H. Aasebo U. Reduced pulmonary function is associated with lower levels of endogenous total and free testosterone. The Tromso study.Eur J Epidemiol. 2007; 22: 107-112Crossref PubMed Scopus (0) Google Scholar, 12Wenzel S.E. Robinson C.B. Leonard J.M. Panettieri Jr., R.A. Nebulized dehydroepiandrosterone-3-sulfate improves asthma control in the moderate-to-severe asthma results of a 6-week, randomized, double-blind, placebo-controlled study.Allergy Asthma Proc. 2010; 31: 461-471Crossref PubMed Scopus (51) Google Scholar, 13Cephus J.Y. Stier M.T. Fuseini H. Yung J.A. Toki S. Bloodworth M.H. et al.Testosterone attenuates group 2 innate lymphoid cell-mediated airway inflammation.Cell Rep. 2017; 21: 2487-2499Abstract Full Text Full Text PDF PubMed Scopus (179) Google Scholar, 14Espinoza J. Montano L.M. Perusquia M. 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Open table in a new tab cGMP, Cyclic guanosine monophosphate; ILC210, IL-10–producing ILC2; MaR1, maresin-1; NF-κB, nuclear factor-κB; RvE1, resolvin E1. Endogenous glucocorticoids suppress inflammation in asthma through multiple molecular mechanisms, including activation of anti-inflammatory genes, repression of proinflammatory genes, and posttranscriptional modifications.2Barnes P.J. Glucocorticosteroids: current and future directions.Br J Pharmacol. 2011; 163: 29-43Crossref PubMed Scopus (396) Google Scholar The diurnal patterns of endogenous glucocorticoids, such as cortisone and cortisol, are abnormal in asthmatic patients at baseline and during an exacerbation. For instance, asthmatic patients with a persistent asthma exacerbation have increased levels of serum cortisone in the afternoon compared with the levels in asthmatic patients in remission.60Fujitaka M. Nomura S. Sakura N. Ueda K. Matuura R. Yumiba C. Morning and afternoon serum levels of cortisone and cortisol in asthmatic patients.Clin Chim Acta. 2000; 299: 101-108Crossref PubMed Scopus (0) Google Scholar Asthmatic patients also have higher cortisol levels and cortisol-to-cortisone ratios after an inhaled allergen challenge than healthy control subjects do. In asthmatic patients, higher baseline cortisol levels were correlated with rapid recovery in FEV1 value. Conversely, asthmatic patients with late-phase reactions had lower cortisol levels.61Peebles Jr., R.S. Togias A. Bickel C.A. Diemer F.B. Hubbard W.C. Schleimer R.P. Endogenous glucocorticoids and antigen-induced acute and late phase pulmonary responses.Clin Exp Allergy. 2000; 30: 1257-1265Crossref PubMed Scopus (0) Google Scholar An increase in late-phase reactions was also observed after cortisol depletion in an experimental dog model of biphasic bronchoconstriction.62Sasaki H. Yanai M. Shimura S. Okayama H. Aikawa T. Sasaki T. et al.Late asthmatic response to Ascaris antigen challenge in dogs treated with metyrapone.Am Rev Respir Dis. 1987; 136: 1459-1465Crossref PubMed Google Scholar Interestingly, cortisol suppression in humans has been shown to enhance IgE-dependent inflammatory processes.63Herrscher R.F. Kasper C. Sullivan T.J. Endogenous cortisol regulates immunoglobulin E-dependent late phase reactions.J Clin Invest. 1992; 90: 596-603Crossref PubMed Google Scholar Local factors in the human lung can also regulate endogenous glucocorticoid activation and inactivation.3Schleimer R.P. Potential regulation of inflammation in the lung by local metabolism of hydrocortisone.Am J Respir Cell Mol Biol. 1991; 4: 166-173Crossref PubMed Google Scholar For instance, 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) catalyzes the conversion of inactive cortisone to active cortisol.64Morgan S.A. McCabe E.L. Gathercole L.L. Hassan-Smith Z.K. Larner D.P. Bujalska I.J. et al.11beta-HSD1 is the major regulator of the tissue-specific effects of circulating glucocorticoid excess.Proc Natl Acad Sci U S A. 2014; 111: E2482-E2491Crossref PubMed Scopus (201) Google Scholar In contrast, 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2) catalyzes the inactivation of cortisol to cortisone.4Blum A. Maser E. Enzymology and molecular biology of glucocorticoid metabolism in humans.Prog Nucleic Acid Res Mol Biol. 2003; 75: 173-216Crossref PubMed Scopus (21) Google Scholar,5Tomlinson J.W. Walker E.A. Bujalska I.J. Draper N. Lavery G.G. Cooper M.S. et al.11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.Endocr Rev. 2004; 25: 831-866Crossref PubMed Scopus (859) Google Scholar Interestingly, exposure of human airway smooth muscle cells to IL-13 increased mitogen-activated protein kinase (MAPK) signaling and expression of 11β-HSD1. In turn, this led to an increase in the conversion of cortisone to cortisol and downstream glucocorticoid receptor transcriptional activity.6Hu A. Fatma S. Cao J. Grunstein J.S. Nino G. Grumbach Y. et al.Th2 cytokine-induced upregulation of 11beta-hydroxysteroid dehydrogenase-1 facilitates glucocorticoid suppression of proasthmatic airway smooth muscle function.Am J Physiol Lung Cell Mol Physiol. 2009; 296: L790-L803Crossref PubMed Scopus (0) Google Scholar Others have demonstrated that the upregulation of epithelial 11β-HSD2 leads to impaired endogenous glucocorticoid activation, which enables the proinflammatory effects of IL-13.7Josephson M.B. Jiao J. Xu S. Hu A. Paranjape C. Grunstein J.S. et al.IL-13-induced changes in endogenous glucocorticoid metabolism in the lung regulate the proasthmatic response.Am J Physiol Lung Cell Mol Physiol. 2012; 303: L382-L390Crossref PubMed Scopus (13) Google Scholar The enzymatic regulation of the cortisone/cortisol shuttle occurs in the lung's structural cells and immune cells relevant to the pathogenesis of asthma. In murine T lymphocytes, the activation of 11β-HSD1 and the downstream increase in glucocorticoid production can modulate their differentiation, effector functions, and apoptosis.8Zhang T.Y. Ding X. Daynes R.A. The expression of 11 beta-hydroxysteroid dehydrogenase type I by lymphocytes provides a novel means for intracrine regulation of glucocorticoid activities.J Immunol. 2005; 174: 879-889Crossref PubMed Google Scholar Sex steroids can also regulate airway inflammation in asthmatic patients. In humans, lower levels of testosterone are correlated with higher asthma prevalence and lower FEV1 value.9Bulkhi A.A. Shepard 2nd, K.V. Casale T.B. Cardet J.C. Elevated testosterone is associated with decreased likelihood of current asthma regardless of sex.J Allergy Clin Immunol Pract. 2020; 8 (35.e4): 3029Abstract Full Text Full Text PDF PubMed Scopus (18) Google Scholar, 10Mohan S.S. Knuiman M.W. Divitini M.L. James A.L. Musk A.W. Handelsman D.J. et al.Higher serum testosterone and dihydrotestosterone, but not oestradiol, are independently associated with favourable indices of lung function in community-dwelling men.Clin Endocrinol (Oxf). 2015; 83: 268-276Crossref PubMed Scopus (48) Google Scholar, 11Svartberg J. Schirmer H. Medbo A. Melbye H. Aasebo U. Reduced pulmonary function is associated with lower levels of endogenous total and free testosterone. 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