Portal de Periódicos da CAPES

Critical period for alveologenesis and early determinants of adult pulmonary disease

2004; American Physical Society; Volume: 287; Issue: 4 Linguagem: Inglês

10.1152/ajplung.00166.2004

1522-1504

Donald Massaro, G. D. Massaro,

Chronic Obstructive Pulmonary Disease (COPD) Research

EDITORIAL FOCUSCritical period for alveologenesis and early determinants of adult pulmonary diseaseDonald Massaro, and Gloria DeCarlo MassaroDonald Massaro, and Gloria DeCarlo MassaroPublished Online:01 Oct 2004https://doi.org/10.1152/ajplung.00166.2004MoreFiguresReferencesRelatedInformationSectionsGRANTSDISCLOSURESAUTHOR NOTESPDF (27 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat as the twig is bentAlexander Popele cras et al., in one of the current articles in focus (Ref. 25, see p. L718 in this issue), synthesized divergent studies about transforming growth factor (TGF)-α pointing to its overexpression in important developmental and adult pulmonary diseases and performed an elegant, clinically and biologically important study (25). They show very brief overexpression of TGF-α by the lung, if produced when the gas-exchange saccules of the architecturally immature lung are being subdivided (septated) to form alveoli, permanently disrupts septation (25). More broadly, their results support the existence of a “critical” period for septation (3, 4, 19, 33, 34, 39, 43, 48) and for the formation of the pulmonary vasculature (26–29, 44, 53) and provide additional evidence early events can influence later lung anatomy (38), lung function (40, 41), and the development of lung disease (9, 52).Precocial animals, e.g., guinea pigs and range animals, septate as fetuses (11, 24); altricial animals septate after birth (1, 7, and for additional references 33, 36). The usual laboratory mouse and rat septate from about postnatal day 4 to 14 but mainly from postnatal day 4 to 7 (7). Strikingly, in all species reported, septation, whether prenatal or postnatal, occurs during a period when the organism's blood concentration of its major glucocorticosteroid hormone is low; septation ends (1, 4, 7, 11, 34, 37) as the glucocorticosteroid concentration rises (17, 18, 23). Administration of a glucocorticosteroid to rats (4, 34, 37) or mice (19) during the period of septation, when the concentration of corticosteroids in the blood is normally low, impairs spontaneous septation and the development of the pulmonary vasculature, resulting in pulmonary hypertension (28). There is neither spontaneous post hoc septation (4, 19, 34, 37) nor spontaneous post hoc vasculogenesis (28), thereby demonstrating a critical period for these developmental events. Put differently, once the molecular processes responsible for these architectural processes are disrupted, they are not spontaneously reconstituted. Microarray analysis of lung gene expression identified downregulation of VEGF receptor-2 with the inhibition of septation by dexamethasone (10). Now Le Cras et al. (25) report another molecule (TGF-α), one whose overexpression in lung, when its concentration is normally low, permanently impairs spontaneous septation.The paper by Le Cras et al. (25) also brings to mind additional aspects of critical periods. Treatments, or altered signaling, applied at the same chronological age may, based on sexual differences in the timing of development, have an effect in one sex but not the other. For example, the responsiveness of rats to prenatal treatment with dexamethasone, which given prenatally depresses the postnatal increase of alveolar surface area, appears earlier in females than in male fetuses (35). In a similar vein, inhibition of signaling by FGF in the fetal, but not postnatal, lung results in altered alveolar architecture in adult lungs (20). Clearly, timing is key.Exposure to other than a sea-level Po2, either experimentally, as part of medical treatment, or by virtue of place of birth, diminishes septation (3, 6, 8, 16, 39, 49). A “high” oxygen tension need only be relative to the organism's stage of development. Thus premature birth into room air at sea level results in entry, before the lung's antioxidant defenses are fully developed (15), into relative hyperoxia, which causes, or contributes to, arrested alveologenesis (31, 49, 50). Exposure to absolute hyperoxia (6), or to a low Po2 (3, 39), impairs septation and is not followed by post hoc spontaneous septation when the organism is placed in 20% O2 and allowed to develop further (3, 39). The molecular deficits responsible for these impairments are largely unknown.It is especially interesting, and may be clinically important, that Fawn-Hooded rats raised at high altitude (e.g., Denver, 5,000 ft) septate less than those of the same strain raised at sea level (16, 26, 27). Although those native to high altitude for centuries have adapted extraordinarily well (21), the meager anatomical data available suggest even they have large alveoli and hence may have impaired septation (8, 49). If the latter is the case, it would result in a diminished number of alveolar attachments to small conducting airways (3), which could explain (47) the lower upstream conductance and higher residual volume (21) in highlanders compared with lowlanders (5).One of the most impressive effects of overexpressing TGF-α is a very low lung tissue elastic recoil (25). This and the less severely low recoil of lungs of rats treated with dexamethasone during the period of septation (34) indicate these manipulations alter development of extracellular matrix. Because collagen exerts its major effect on recoil at high lung volumes (22), the very large lungs of mice overexpressing TGF-α probably are due mainly to altered collagen (25). Defective lung elastin, as seems to exist in mice that overexpress TGF-α (25), would diminish recoil in the tidal volume range (22).The functional evidence of altered extracellular matrix in mice overexpressing TGF-α (25) and in dexamethasone-treated rat pups (34), as well as the rapid thinning and altered composition of the alveolar wall in dexamethasone-treated rats, (32) raises the obvious possibility that abnormal extracellular matrix contributes, perhaps in a major way, to impaired alveologenesis. This notion is supported by finding that exposure to hypoxia shortly after birth results in adult rats that had failed to septate as pups (3, 39) and that have diminished lung elastic recoil (41). Interestingly, loss of lung recoil occurs during acclimatization of adults to high altitude (30).The work by Le Cras et al. (25), importantly, also points to the impact early events have on the subsequent development of lung disease and adds to our meager understanding of the molecular basis of this effect. Others have provided clinical and experimental examples of late consequences of early events, including the very important observation that intrauterine and postnatal exposure to parental tobacco smoking is associated in adulthood with more respiratory symptoms, poorer lung function, and increased risk for obstructive lung disease than found in those not exposed (52). Similarly, viral bronchial and alveolar infections, common among infants, when produced in neonatal rats are associated with diminished alveolar surface area and bronchiolar hypoplasia in adult rats (9). One-quarter of children in a 24-block, very-low-income area of central Harlem in New York City, have asthma, which is generally attributed to allergens from insects (42). We wonder if early events aggravate or create a predisposition to the bronchial response to allergens. In particular, does a stressful environment during pregnancy mean maternal hypercorticism? If so, does it result in postnatal diminished airway growth and later low airway conductance in humans, as it does in ferrets (13)? Does very early inadequate nutrition, which causes a later lower-than-normal number of ciliated cells in conducting airways of rats (38), also contribute to asthma in humans? The impact of early deleterious events on the later response to the environment is, in our opinion, a very understudied area of lung biology.Late effects of early events may be relevant to the great variation of the number of alveoli among adults without lung disease, which exists even when the number of alveoli is corrected for body length and lung volume (2). These differences could result from early illnesses, generally considered harmless, e.g., febrile episodes, which, in fact, may elevate the blood's corticosteroid concentration (51), and viral infections (9). Furthermore, differences in the number of alveoli per lung volume due to early events could influence the rate of progression of diseases associated with alveolar loss, e.g., could, at least partly, determine among individuals with chronic obstructive pulmonary disease, who is a rapid or a slow loser of forced expiratory volume (14). Because alveolar surface area is progressively lost beginning in the third decade (54) and because birth at altitude seems to result in impaired septation (8, 49), we wonder if the exodus of elderly from high altitude (45) is due, in some measure, to birth at altitude and the consequent presence of fewer alveoli (we recognize not all of the elderly who leave high altitude were born at high altitude). Equally interesting is the increased prevalence of chronic obstructive pulmonary disease at high altitude (12, 46), which could reflect early damage to the lung's extracellular matrix.Thus Le Cras et al. (25) have brought into view three underappreciated, understudied, but fascinating and important areas of lung biology and medicine: a critical period for septation, the role the stage of development has on the later impact of untoward events, and the effect of early events on the later development of disease. The challenge for all of us is to further understand the biology of these events and to develop means to prevent, or reverse, their untoward effects.GRANTSThis work was supported in part by National Heart, Lung, and Blood Institute Grants HL-20366 and HL-37666.DISCLOSURESD. Massaro and G. D. Massaro hold a patent for the use of retinoids in lung diseases.D. Massaro is Cohen Professor at Georgetown University.AUTHOR NOTESAddress for reprint requests and other correspondence: D. Massaro, Lung Biology Lab, Box 571481, Preclinical Science Bldg., GM-12, Georgetown Univ. School of Medicine, 3900 Reservoir Rd., NW, Washington, DC 20057-1481 (E-mail: massarod@georgetown.edu) Download PDF Previous Back to Top Next FiguresReferencesRelatedInformationREFERENCES1 Amy RW, Bowes D, Burri PH, Haines J, and Thurlbeck WM. Postnatal growth of the mouse lung. J Anat 124: 131–151, 1977.PubMed | ISI | Google Scholar2 Angus GE and Thurlbeck M. Number of alveoli in the human lung. J Appl Physiol 32: 483–485, 1972.Link | ISI | Google Scholar3 Blanco LN, Massaro D, and Massaro GD. Alveolar size, number, and surface area: developmentally dependent response to 13% O2. Am J Physiol Lung Cell Mol Physiol 261: L370–L377, 1991.Link | ISI | Google Scholar4 Blanco LN, Massaro GD, and Massaro D. Alveolar dimensions and number: developmental and hormonal regulation. Am J Physiol Lung Cell Mol Physiol 257: L240–L247, 1989.Google Scholar5 Brody JS, Lahiri S, Simpser M, Motoyama EK, and Velasquez T. Lung elasticity and airway dynamics in Peruvian natives to high altitude. J Appl Physiol 42: 245–251, 1977.Link | ISI | Google Scholar6 Bucher JR and Roberts RJ. The development of the new born rat lung in hyperoxia: a dose response study of lung growth, maturation, and changes in antioxidant enzyme activity. Pediatr Res 15: 999–1008, 1981.Crossref | PubMed | ISI | Google Scholar7 Burri PH, Dbaly J, and Weibel ER. The postnatal growth of the rat lung. I. Morphometry. Anat Rec 178: 711–730, 1974.Crossref | PubMed | Google Scholar8 Campos Rey De Castro J and Iglesias B. Mechanisms of natural acclimatization: preliminary report on anatomic studies at high altitudes. US Air Force Sch Med Rep: 55–97, 1956.Google Scholar9 Castleman WL, Sorkness RL, Lemanske RF, Grasee G, and Suyemoto MM. Neonatal viral bronchiolitis and pneumonia induces bronchiolar hypoplasia and alveolar dysplasia in rats. Lab Invest 59: 387–396, 1988.PubMed | ISI | Google Scholar10 Clerch LB, Baras AS, Massaro GD, Hoffman EP, and Massaro D. DNA microarray analysis of neonatal mouse lung connects regulation of KDR with dexamethasone-induced inhibition of alveolar formation. Am J Physiol Lung Cell Mol Physiol 286: L411–L419, 2004.Link | ISI | Google Scholar11 Collins MH, Kleinerman J, Mossinger AC, Collins AH, James LS, and Blanc WA. Morphometric analysis of the growth of the normal fetal guinea pig lung. Anat Rec 216: 381–391, 1986.Crossref | PubMed | Google Scholar12 Cote TR, Stroup DF, Dwyer DM, Horan JM, and Peterson DE. Chronic obstructive pulmonary disease mortality: a role for altitude. Chest 103: 1194–1197, 1993.Crossref | PubMed | ISI | Google Scholar13 Ellington B, McBride JT, and Stokes DC. Effects of corticosteroids on postnatal lung and airway growth in the ferret. J Appl Physiol 68: 2029–2033, 1990.Link | ISI | Google Scholar14 Fletcher C, Peto R, Tinker C, and Struhl K. The Natural History of Chronic Bronchitis and Emphysema. New York: Oxford University Press, 1976, p. 71–73.Google Scholar15 Frank L and Groseclose EE. Preparation for birth into an O2-rich environment: the antioxidant enzymes in the developing rabbit lung. Pediatr Res 18: 240–244, 1984.Crossref | PubMed | ISI | Google Scholar16 Gebb SA, Oka M, Nagaoka T, and Jones PL. Rho/Rho-kinase enhances alveolarization and tenascin-C deposition in the Fawn-hooded rat (Abstract). FASEB J 18: A712, 2004.Google Scholar17 Henning SJ. Plasma concentration of total and free corticosterone during development in the rat. Am J Physiol Endocrinol Metab Gastrointest Physiol 235: E451–E456, 1978.PubMed | ISI | Google Scholar18 Henning SJ. Postnatal development: coordination of feeding, digestion, and metabolism. Am J Physiol Gastrointest Liver Physiol 241: G199–G214, 1981.Link | ISI | Google Scholar19 Hind M and Maden M. Retinoic acid induces alveolar regeneration in the adult mouse. Eur Respir J 23: 20–27, 2004.Crossref | PubMed | ISI | Google Scholar20 Hokuto I, Perl AK, and Whitsett JA. Prenatal, but not postnatal, inhibition of fibroblast growth factor receptor signaling causes emphysema. J Biol Chem 278: 415–421, 2003.Crossref | PubMed | ISI | Google Scholar21 Hurtado A. Animals in high altitudes: resident man. In: Handbook of Physiology. Adaptation to the Environment. Washington, DC: Am. Physiol. Soc, 1964, sect. 4, chapt. 54, p. 843–860.Google Scholar22 Johanson W Jr and Pierce AK. Effects of elastase, collagenase, and papain on structure and function of rat lungs in vitro. J Clin Invest 51: 288–293, 1972.Crossref | PubMed | ISI | Google Scholar23 Jones CT. Corticosteroid concentrations in the plasma of fetal and maternal guinea pigs during gestation. Endocrinology 95: 1129–1133, 1974.Crossref | PubMed | ISI | Google Scholar24 Lechner AJ and Banchero N. Advanced pulmonary development in newborn guinea pigs (Cavia porcellus). Am J Anat 163: 235–246, 1982.Crossref | PubMed | Google Scholar25 Le Cras TD, Hardie WD, Deutsch GH, Albertine KH, Ikegami M, Whitsett JA, and Korfhagen TR. Transient induction of TGF-α disrupts lung morphogenesis, causing pulmonary disease in adulthood. Am J Physiol Lung Cell Mol Physiol 287: L718–L729, 2004.Link | ISI | Google Scholar26 Le Cras TD, Kim DH, Gebb S, Markham NE, Shannon JM, Tuder RM, and Abman SH. Abnormal lung growth and the development of pulmonary hypertension in the Fawn-Hooded rat. Am J Physiol Lung Cell Mol Physiol 277: L709–L718, 1999.Link | ISI | Google Scholar27 Le Cras TD, Kim DH, Markham NE, and Abman SH. Early abnormalities in pulmonary vascular development in the Fawn-hooded rat raised at Denver's altitude. Am J Physiol Lung Cell Mol Physiol 279: L283–L291, 2000.Link | ISI | Google Scholar28 Le Cras TD, Markham NE, Morris KG, Ahrens CR, McMurtry IF, and Abman SH. Neonatal dexamethasone treatment increases the risk for pulmonary hypertension in adult rats. Am J Physiol Lung Cell Mol Physiol 278: L822–L829, 2000.PubMed | ISI | Google Scholar29 Le Cras TD, Markham NE, Tuder RM, Voelkel NF, and Abman SH. Treatment of newborn rats with a VEGF receptor inhibitor causes pulmonary hypertension and abnormal lung structure. Am J Physiol Lung Cell Mol Physiol 283: L555–L562, 2002.Link | ISI | Google Scholar30 Mansell A, Powles A, and Sutton J. Changes in pulmonary PV characteristics of human subjects at altitude of 5,366 m. J Appl Physiol 49: 79–83, 1980.Link | ISI | Google Scholar31 Margraf LR, Tomashefski JR Jr, Bruce MC, and Dahms BB. Morphometric analysis of the lung in bronchopulmonary dysplasia. Am Rev Respir Dis 143: 391–400, 1991.Crossref | PubMed | ISI | Google Scholar32 Massaro D and Massaro GD. Dexamethasone accelerates postnatal alveolar wall thinning and alters wall composition. Am J Physiol Regul Integr Comp Physiol 251: R218–R224, 1986.Link | ISI | Google Scholar33 Massaro D and Massaro GD. Pulmonary alveoli: formation, the “call for oxygen,” and other regulators. Am J Physiol Lung Cell Mol Physiol 282: L345–L358, 2002.Link | ISI | Google Scholar34 Massaro D, Teich N, Maxwell S, Massaro GD, and Whitney P. Postnatal development of alveoli. Regulation and evidence for a critical period in rats. J Clin Invest 76: 1297–1305, 1985.Crossref | PubMed | ISI | Google Scholar35 Massaro GD and Massaro D. Formation of alveoli in rats: postnatal effect of prenatal dexamethasone. Am J Physiol Lung Cell Mol Physiol 263: L37–L41, 1992.Link | ISI | Google Scholar36 Massaro GD and Massaro D. Formation of pulmonary alveoli and gas-exchange surface area: quantitation and regulation. Annu Rev Physiol 58: 73–92, 1996.Crossref | PubMed | ISI | Google Scholar37 Massaro GD and Massaro D. Retinoic acid treatment partially rescues failed septation in rats and in mice. Am J Physiol Lung Cell Mol Physiol 278: L955–L960, 2000.Link | ISI | Google Scholar38 Massaro GD, McCoy L, and Massaro D. Postnatal undernutrition slows development of bronchiolar epithelium in rats. Am J Physiol Regul Integr Comp Physiol 255: R521–R526, 1988.Link | ISI | Google Scholar39 Massaro GD, Olivier J, Dzikowski C, and Massaro D. Postnatal development of lung alveoli: suppression by 13% O2 and a critical period. Am J Physiol Lung Cell Mol Physiol 258: L321–L327, 1990.Link | ISI | Google Scholar40 Okubo S and Mortola JP. Long-term respiratory effects of neonatal hypoxia in the rat. J Appl Physiol 64: 952–958, 1988.Link | ISI | Google Scholar41 Okubo S and Mortola JP. Respiratory mechanics in adult rat hypoxia in the neonatal period. J Appl Physiol 66: 1772–1778, 1989.Link | ISI | Google Scholar42 Pérez-Peña R. Study finds asthma in 25% of children in central Harlem. New York Times, April 19, 2003.Google Scholar43 Perl AK, Hokuto I, Impagnatiello MA, Christofori G, and Whitsett JA. Temporal effects of Sprouty on lung morphogenesis. Dev Biol 258: 154–168, 2003.Crossref | PubMed | ISI | Google Scholar44 Rabinovitch M, Gamble WJ, Miettinen OS, and Reid L. Age and sex influence on pulmonary hypertension of chronic hypoxia and on recovery. Am J Physiol Heart Circ Physiol 240: H62–H72, 1981.Link | ISI | Google Scholar45 Regensteiner JG and Moore LG. Migration of the elderly from high altitudes in Colorado. JAMA 253: 3124–3128, 1985.Crossref | PubMed | ISI | Google Scholar46 Renzetti AD Jr, McClement JH, and Litt BD. The Veterans Administration cooperative study of pulmonary function. Am J Med 41: 115–129, 1966.Crossref | PubMed | ISI | Google Scholar47 Saetta M, Ghezzo H, Kim WD, King M, Angus GE, Wang NS, and Cosio MG. Loss of alveolar attachments in smokers. A morphometric correlate of lung function impairment. Am Rev Respir Dis 132: 894–900, 1985.PubMed | ISI | Google Scholar48 Sahebjami H and Domino M. Effects of postnatal dexamethasone treatment on development of alveoli in adult rats. Exp Lung Res 15: 961–73, 1989.Crossref | PubMed | ISI | Google Scholar49 Saldana M and Garcia-Oyola E. Morphometry of the high altitude lung (Abstract). Lab Invest 22: 509, 1970.ISI | Google Scholar50 Sobonya RE, Logrinoff MM, Taussig LM, and Theriault A. Morphometric analysis of the lung in prolonged bronchopulmonary dysplasia. Pediatr Res 16: 969–72, 1982.Crossref | PubMed | ISI | Google Scholar51 Stith RD and Templer LA. Peripheral endocrine and metabolic responses to centrally administered interleukin-1. Neuroendocrinology 60: 215–24, 1994.Crossref | PubMed | ISI | Google Scholar52 Svanes C, Omenaas E, Jarvis D, Chinn S, Gulsvik, and Burney P. Parental smoking in childhood and adult obstructive lung disease: results from the European Community Respiratory Health Survey. Thorax 4: 295–302, 2004.Google Scholar53 Tang JR, Le Cras TD, Morris KG Jr, and Abman SH. Brief perinatal hypoxia increases severity of pulmonary hypertension after reexposure to hypoxia in infant rats. Am J Physiol Lung Cell Mol Physiol 278: L356–L364, 2000.Link | ISI | Google Scholar54 Thurlbeck WM. The internal surface area of nonemphysematous lung. Am Rev Respir Dis 95: 765–773, 1967.PubMed | ISI | Google Scholar Cited ByInflammatory blockade prevents injury to the developing pulmonary gas exchange surface in preterm primatesScience Translational Medicine, Vol. 14, No. 638Analysis of interleukins 6, 8, 10 and 17 in the lungs of premature neonates with bronchopulmonary dysplasiaCytokine, Vol. 131Gestation and lactation exposure to nicotine induces transient postnatal changes in lung alveolar developmentSanja Blaskovic,* Yves Donati,* Filippo Zanetti, Isabelle Ruchonnet-Métrailler, Sylvain Lemeille, Tiziana P. Cremona, Johannes C. Schittny, and Constance Barazzone-Argiroffo19 March 2020 | American Journal of Physiology-Lung Cellular and Molecular Physiology, Vol. 318, No. 4Immune modulators for the therapy of BPDModulators of inflammation in Bronchopulmonary DysplasiaSeminars in Perinatology, Vol. 42, No. 7Inhibition of pulmonary β-carotene 15, 15’-oxygenase expression by glucocorticoid involves PPARα21 July 2017 | PLOS ONE, Vol. 12, No. 7Secreted Phosphoprotein 1 Is a Determinant of Lung Function Development in MiceAmerican Journal of Respiratory Cell and Molecular Biology, Vol. 51, No. 5Lung Development Alterations in Newborn Mice after Recovery from Exposure to Sublethal HyperoxiaThe American Journal of Pathology, Vol. 184, No. 4Neonatal steroids induce a down-regulation of tenascin-C and elastin and cause a deceleration of the first phase and an acceleration of the second phase of lung alveolarization4 August 2013 | Histochemistry and Cell Biology, Vol. 141, No. 1Early life influences on the development of chronic obstructive pulmonary disease25 February 2013 | Therapeutic Advances in Respiratory Disease, Vol. 7, No. 3Lung effects of inhaled corticosteroids in a rhesus monkey model of childhood asthma15 June 2012 | Clinical & Experimental Allergy, Vol. 42, No. 7Is a regenerative approach viable for the treatment of COPD?6 April 2011 | British Journal of Pharmacology, Vol. 163, No. 1Dexamethasone and Betamethasone for Prenatal Lung Maturation: Differences in Vascular Endothelial Growth Factor Expression and Alveolarization in RatsNeonatology, Vol. 100, No. 1Early childhood weight status in relation to asthma development in high-risk childrenJournal of Allergy and Clinical Immunology, Vol. 126, No. 6Inflammation and Organ FailurePostnatal cardiopulmonary adaptations to high altitudeRespiratory Physiology & Neurobiology, Vol. 158, No. 2-3Elevated Exhaled Nitric Oxide in Newborns of Atopic Mothers Precedes Respiratory SymptomsAmerican Journal of Respiratory and Critical Care Medicine, Vol. 174, No. 12Pathogenesis of Bronchopulmonary DysplasiaSeminars in Perinatology, Vol. 30, No. 4Expression of the Reverse Tetracycline-Transactivator Gene Causes Emphysema-Like Changes in MiceAmerican Journal of Respiratory Cell and Molecular Biology, Vol. 34, No. 5Effects of viral respiratory infections on lung development and childhood asthmaJournal of Allergy and Clinical Immunology, Vol. 115, No. 4 More from this issue > Volume 287Issue 4October 2004Pages L715-L717 Copyright & PermissionsCopyright © 2004 the American Physiological Societyhttps://doi.org/10.1152/ajplung.00166.2004PubMed15355862History Published online 1 October 2004 Published in print 1 October 2004 Metrics Downloaded 227 times 24 CITATIONS 24 Total citations 1 Recent citation 3.41 Field Citation Ratio 0.59 Relative Citation Ratio publications27supporting0mentioning18contrasting0Smart Citations270180Citing PublicationsSupportingMentioningContrastingView CitationsSee how this article has been cited at scite.aiscite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.