Cavazza, A

Graziano, P

Papotti, Mauro Giulio

Rossi, G

English

Institutional Research Information System University of Turin

Author disclosures are available with the text of this letter at www.atsjournals.org.Philip G. Bardin, Ph.D.Kathy Low, M.B.B.S.Peter Holmes, M.B.B.S.Garun Hamilton, Ph.D.Monash University and Medical CentreMelbourne, AustraliaReferences1. Christopher KL, Wood RP, Eckert CR, Blager FB, Raney RA, SouhradaJF. Vocal cord dysfunction presenting as asthma. N Engl J Med 1983;308:1566–1570.2. Low K, Lau KK, Holmes P, Crossett M, Vallance N, Phyland D, HamzaK, Hamilton G, Bardin PG. Abnormal vocal cord function in difficult-to-treat asthma. Am J Respir Crit Care Med 2011;184:50–56.3. Braunstahl G-J. United airways concept. Proc Am Thorac Soc 2009;6:652–654.Copyright ª 2012 by the American Thoracic SocietymTOR/p70S6K in Diffuse Idiopathic PulmonaryNeuroendocrine Cell HyperplasiaTo the Editor:We read with interest the review article by Nassar and coworkers(1) on diffuse idiopathic pulmonary neuroendocrine cell hyperpla-sia (DIPNECH). As correctly reported by the authors, thisuncommon, possibly underrated, and often indolent disease maylead to severe respiratory obstructive symptoms and finally todeath. In symptomatic patients, therapeutic options are limitedto steroids, surgical lung resections, and lung transplantation.Whatever the pathogenesis underlying the occurrence ofDIPNECH, respiratory functions were deteriorated by a diffuseconstrictive bronchiolitis secondary to fibrogenic peptides pro-duced by the proliferating neuroendocrine cells (2, 3).Pulmonary and extrapulmonary neuroendocrine cell prolif-erations are characterized by a consistent expression of somato-statin receptors (SSR) (mainly types 2 and 5) and of mammaliantarget of rapamycin (mTOR) (4). These findings representa solid scientific rationale in explaining the good clinical resultsrecently reported with selective somatostatin analogs andmTOR inhibitors in neuroendocrine tumors (5). Little is knownabout the expression of SSR and mTOR in DIPNECH. Gorsh-tein and colleagues (6) recently highlighted the important roleof SSR in DIPNECH showing a high uptake in all 11 casestested by 111In-pentetreotide scintigraphy (Octreoscan) orgallium-68 (68Ga) 1,4,7,10-tetra-azacyclododecane-N,N9,N99,N999-tetraacetic acid-Tyr3-octreotide/Na3-octreotide 68Ga-labeled 1,4,7,10-tetraazacyclododecane-N,N9,N,N9-tetraaceticacid positron emission/computed tomography imaging. In addi-tion, six patients with progressive respiratory symptoms treatedwith somatostatin analogs experienced disease stabilization withconsistent improvement of respiratory functions in four cases.To our knowledge, there are no data aboutmTOR-relatedmol-ecule expression in DIPNECH. By immunohistochemistry, wetested phosphorylated-mTOR (p-mTOR) and its major target,namely the ribosomal p70S6-kinase (p70S6K), in four casesof DIPNECH collected from our archival files. All these caseswere characterized by the presence of a typical carcinoid andfoci of neuroendocrine hyperplasia as well as tumorlets. On im-munohistochemistry, a robust and diffuse expression of p-mTORand p70S6K was observed in all neuroendocrine lesions. Thus,the activation of mTOR pathway in DIPNECH seems to be en-tirely similar to what has been observed in sporadic carcinoidtumors (4).Although preliminary, these results seem to support a scien-tific rationale in adopting mTOR inhibitors in DIPNECH andthen to widen the spectrum of therapeutic tools in this intriguingdisease.Author disclosures are available with the text of this letter at www.atsjournals.org.Giulio Rossi, M.D.Azienda PoliclinicoModena, ItalyAlberto Cavazza, M.D.Arcispedale St. Maria NuovaReggio Emilia, ItalyPaolo Graziano, M.D.San Camillo-Forlanini HospitalRoma, ItalyMauro Papotti, M.D.University of Torino at San Luigi HospitalOrbassano/Torino, ItalyReferences1. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM,Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cell hy-perplasia: a systematic overview. Am J Respir Crit Care Med 2011;184:8–16.2. Aguayo SM, Miller YE, Waldron JA Jr, Bogin RM, Sunday ME, StatonGW Jr, Beam WR, King TE Jr. Brief report: idiopathic diffuse hyper-plasia of pulmonary neuroendocrine cells and airways disease. N EnglJ Med 1992;327:1285–1288.3. Davies SJ, Gosney JR, Hansell DM, Wells AU, du Bois RM, Burke MM,Sheppard MN, Nicholson AG. Diffuse idiopathic pulmonary neuro-endocrine cell hyperplasia: an under-recognized spectrum of disease.Thorax 2007;62:248–252.4. Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M.Mammalian target of rapamycin signaling activation patterns inneuroendocrine tumors of the lung. Endocr Relat Cancer 2010;17:977–987.5. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis,and treatment of gastroenteropancreatic neuroendocrine tumors. CACancer J Clin 2011;61:113–132.6. Gorshtein A, Gross DJ, Barak D, Sternov Y, Refaeli Y, Shimon I,Grozinsky-Glasberg S. Diffuse idiopathic pulmonary neuroendocrinecell hyperplasia and the associated lung neuroendocrine tumors.Cancer (In press)Copyright ª 2012 by the American Thoracic SocietyFrom the Authors:We appreciate the interest and comments by Dr. Rossi and col-leagues regarding our article (1). As with many diseases, aware-ness and recognition encourage progress in treatment. Recentpublications and discussions within the past year have broughtto the forefront treatment strategies in extrapulmonary neuroen-docrine tumors that may be relevant to pulmonary proliferationsexpressing somatostatin receptors (SSR) (2, 3). Although little isknown about the expression of SSR and mammalian target ofrapamycin (mTOR) in DIPNECH, the information highlightedby Gorshtein, Righi, and colleagues (4, 5) complements our clin-ical paper and illustrates the need to better understand the im-portant role of somatostatin analogs (SSA) and their potential fortreatment in DIPNECH. Neuroendocrine cell proliferation withsomatostatin receptor expression is the fundamental pathologicresponse to probable injury, so it makes teleological sense thatSSA may be beneficial in the therapeutic paradigm.The discussion of immunohistochemistry evidence, includingthe activation of the mTOR pathway in DIPNECH, is anCorrespondence 341excellent example of the progress that can be made with recog-nition and international collaboration on this disease. Theseleads may result in successful treatment strategies utilizingmTOR inhibitors in DIPNECH.Another point of importance is the role of octreotide analogradio-labeled nuclear scintigraphy with positron emission/computed tomography imaging (6) in perhaps guiding treatmentwhere the density of SSR in DIPNECH patients may predicttherapeutic success with SSA.As with most uncommon and often unrecognized diseases,collaboration may be the only way to obtain the volume ofpatients required to properly strategize and assess treatments.True progress and treatment algorithms would be best servedwith the establishment of an international registry for patients,a tissue repository, and the synergy of knowledge and experiencebetween institutions.Author disclosures are available with the text of this letter at www.atsjournals.org.D. E. Jaroszewski, M.D., M.B.A.F. Mookadam, M.B., B.Ch., M.Sc.Mayo Clinic ArizonaScottsdale, ArizonaA. A. Nassar, M.D.University of California San DiegoSan Diego, CaliforniaReferences1. Nassar AA, Jaroszewski DE, Helmers RA, Colby TV, Patel BM,Mookadam F. Diffuse idiopathic pulmonary neuroendocrine cellhyperplasia: a systematic overview. Am J Respir Crit Care Med 2011;184:8–16.2. Turaga KK, Kvols LK. Recent progress in the understanding, diagnosis,and treatment of gastroenteropancreatic neuroendocrine tumors. CACancer J Clin 2011;61:113–132.3. Cameron CM, Roberts F, Connell J, Sproule MW. Diffuse idiopathicpulmonary neuroendocrine cell hyperplasia: an unusual cause of cy-clical ectopic adrenocorticotrophic syndrome. Br J Radiol 2011;84:e14–e17.4. Gorshtein A, Gross DJ, Barak D, Strenov Y, Refaeli Y, Shimon I,Grozinksky-Glasberg S. Diffuse idiopathic pulmonary neuroendo-crine cell hyperplasia and the associated lung neuroendocrinetumors. Cancer (In press)5. Righi L, Volante M, Rapa I, Tavaglione V, Inzani F, Pelosi G, Papotti M.Mammalian target of rapamycin signaling activation patterns inneuroendocrine tumors of the lung. Endocr Relat Cancer 2010;17:977–987.Copyright ª 2012 by the American Thoracic SocietyCamphor, an Old Cough Remedy witha New MechanismTo the Editor:In an interesting correspondence, Patberg and colleagues (1)have commented on a recent proposal by Birring (2) on unex-plained chronic cough (UCC). The hypothesis regards the roleof the transient receptor potential vanilloid (TRPV)1 channel asa common final pathway underlying the heightened cough sen-sitivity of individuals with UCC. The presence of TRPV1 invagal afferents, the successful use of the selective TRPV1 stim-ulant, capsaicin, as a protussive agent in experimental animalsand humans, and the lower threshold to capsaicin-inducedcough in patients with UCC have suggested (and Dr. Birringhas reconsidered this hypothesis) a central role for TRPV1hyperexpression and hyperfunction in chronic cough. Patbergand coworkers (1) further supported this hypothesis with theobservation that an old cough remedy, camphorated oil, con-tains camphor, which initially stimulates but then stronglydesensitizes TRPV1. Clinical evidence for the antitussive actionof camphor has been also reported in their comment (1). Weagree with the proposed hypothesis and with the implied ther-apeutic perspectives for TRPV1 desensitizers/antagonists. How-ever, camphor can no longer be regarded as a selective agent forTRPV1. Rather, camphor has been identified as a TRPA1 (“A”stands for ankyrin) channel antagonist. TRPA1 is coexpressedwith TRPV1 in nociceptive neurons, including vagal afferents;various TRPA1 agonists, including cinnamaldehyde and acro-lein, cause cough by TRPA1 stimulation in guinea pigs (3) andhumans (4); and camphor reduces TRPA1-mediated cough (3).Also, menthol (mentioned in the comment by Patberg and col-leagues) (1), an agonist of the cold receptor TRPM8 (and viathis mechanism responsible for the fresh sensation associatedwith mint), and traditionally used as a cough remedy, has beenfound to inhibit TRPA1 (5). Thus, while we recognize the pos-sible role of TRPV1 in the mechanism of UCC, we recommendthat the emerging role of TRPA1 not be disregarded. This is ofparticular relevance when considering the peculiar chemicalfeatures of TRPA1, which are responsible for the unique abilityof this channel to sense a series of irritant and reactive endog-enous (associated with inflammation and tissue injury) and ex-ogenous (associated with environmental pollution) molecules,derived from oxidative and nitrative stress (6). Following theadvice of the children’s song “John Brown’s baby had a cough,”the future challenge in drug discovery for the treatment ofchronic cough would be better suited by a compound that moreefficiently and safely combines the blocking property of cam-phor at both TRPV1 and TRPA1.Author disclosures are available with the text of this letter at www.atsjournals.org.Pierangelo Geppetti, M.D.Silvia Benemei, M.D.University of FlorenceFlorence, ItalyRiccardo Patacchini, Ph.D.Chiesi PharmaceuticalsParma, ItalyReferences1. Patberg KW, de Groot JR, Patberg Y. “John Brown’s baby had acough”: a central role for TRPV1? [letter]. Am J Respir Crit Care Med2011;184:382.2. Birring SS. Controversies in the evaluation and management of chroniccough. Am J Respir Crit Care Med 2011;183:708–715.3. Andre E, Gatti R, Trevisani M, Preti D, Baraldi PG, Patacchini R,Geppetti P. Transient receptor potential ankyrin receptor 1 is a noveltarget for pro-tussive agents. Br J Pharmacol 2009;158:1621–1628.4. Birrell MA, Belvisi MG, Grace M, Sadofsky L, Faruqi S, Hele DJ, MaherSA, Freund-Michel V, Morice AH. TRPA1 agonists evoke coughing inguinea pig and human volunteers. Am J Respir Crit Care Med 2009;180:1042–1047.5. Karashima Y, Damann N, Prenen J, Talavera K, Segal A, Voets T, NiliusB. Bimodal action of menthol on the transient receptor potentialchannel TRPA1. J Neurosci 2007;27:9874–9884.6. Bessac BF, Sivula M, von Hehn CA, Escalera J, Cohn L, Jordt SE.TRPA1 is a major oxidant sensor in murine airway sensory neurons.J Clin Invest 2008;118:1899–1910.Copyright ª 2012 by the American Thoracic SocietyAuthor Contributions: All authors have substantially contributed to the draftingand revision of the letter and have approved the version to be published.342 AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE VOL 185 2012

mTOR/p70S6K in Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia.

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mTOR/p70S6K in Diffuse Idiopathic Pulmonary Neuroendocrine Cell Hyperplasia.

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