Alveolar growth and development in childhood measured by helium-3 magnetic resonance

Summary

We investigated the pattern of normal alveolar development in children using the recently developed technique of hyperpolarized helium-3 magnetic resonance (3-He MR). We also analyzed the influence of early life exposures and illnesses on normal alveolar development.

Study description

Disorders which affect fetal and early childhood growth and development increase the risk of lung diseases in adult life, possibly by affecting lung growth and development. Therefore it is important to determine how lungs develop normally and delineate the factors affecting normal lung development. Early life risk factors may increase the risk of chronic obstructive pulmonary disease (COPD), which is the only leading cause of death that is increasing in prevalence worldwide (European Lung White Book, 2003).

The formation of the gas exchanging zone of the lungs, the pulmonary alveoli was thought to be complete by the age of 2-3 years. However, new evidence from animal studies indicates that formation of alveoli continues until physical growth of the lungs stop. 

We used the new, safe, simple and ethical technique, 3-He MR, to establish the normal pattern of growth and development of the alveolar zone of the lungs. The apparent diffusion coefficient (ADC) of Helium measured by this technique is related to alveolar size. If alveolar development was complete by 3 years, as previously believed, alveolar size should increase with lung growth. We explored the relationship between early-life events and exposures, and alveolar growth and development. 

In the future, we will relate the changes we find to standard lung function tests, in order to explore the relationships between structural development and functional development in the lungs. Longitudinal measurements on cohort members will provide information about the potential contributions of childhood events on lung disease in adult life.

Current status

During the last 3 years, we have worked with volunteer children and young people. We have measured their lung volume in Leicester, and then taken them to Nottingham for the 3-He MR. Some of the volunteers have been more than once, which helps us to look at changes in individuals as they grow. We have also studied whether the size of the breath of helium or the final concentration of the helium within the lungs affected the measurement. Two hundred and five children and young people have participated in the study. Most of them were from the Leicestershire cohorts, but we also invited some younger children to make sure we had a wide age range.  One important part of the study was to look at people who had been born prematurely. For this particular part of our work, we studied 38 young people aged 11-13 who had been born extremely early. Half of them had suffered from chronic lung disease – in other words, they needed a lot of help with breathing for some considerable time. The others were less severely affected. We compared the measurements from these with 21 people of the same age who had been born just a few weeks early, and 61 who had been born on time.

Update

We have published our findings regarding alveolar development in children. Lung alveoli do not increase in size as much as expected with lung growth. This can only be explained by continuous alveolar formation in children until lung growth is complete (overturning the previous theory, taught in many textbooks). 

Publications

Dogaru CM, Narayanan M, Spycher BD, Pescatore AM, Owers-Bradley J, Beardsmore CS, Silverman M, Kuehni CE.  
Breastfeeding, lung volumes and alveolar size at school-age.
BMJ Open Respir Res. 2015 Jul 6;2(1):e000081. doi: 10.1136/bmjresp-2015-000081. eCollection 2015.

Narayanan M, Owers-Bradley J, Beardsmore CS, Kuehni CE, Silverman M.
Reply: On the use of 3He diffusion magnetic resonance as evidence of neo-alveolarization during childhood and adolescence. 
Am J Respir Crit Care Med. 2014 Feb 15;189(4):502-4. doi: 10.1164 /rccm. 201311-2032LE. 

Wain LV, Odenthal-Hesse L, Abujaber R, Sayers I, Beardsmore CS, Gaillard EA, Chappell S, Dogaru CM, McKeever T, Guetta-Baranes T, Kalsheker N, Kuehni CE, Hall IP, Tobin MD, Hollox EJ. 
Copy number variation of the beta-defensin genes in europeans: no supporting evidence for association with lung function, chronic obstructive pulmonary disease or asthma
PLoS One. 2014 Jan 3;9(1):e84192. doi: 10.1371/journal.pone.0084192. eCollection 2014.

Narayanan M, Beardsmore CS, Owers-Bradley J, Dogaru CM, Mada M, Ball I, Garipov RR, Kuehni CE, Spycher BD, Silverman M. 
Catch-up Alveolarization in Ex-Preterm Children: evidence from (3)He magnetic resonance 
Am J Respir Crit Care Med. 2013 May 15;187(10):1104-9. doi: 10.1164/rccm.201210-1850OC. 

Strippoli MP, Kuehni CE, Dogaru CM, Spycher BD, McNally T, Silverman M, Beardsmore CS.
Etiology of Ethnic Differences in Childhood Spiromentry 
Pediatrics. 2013 Jun;131(6):e1842-9. doi: 10.1542/peds.2012-3003.

Dogaru CM, Strippoli MP, Spycher BD, Beardsmore CS, Silverman M, Kuehni CE.
Breastfeeding and Lung Function at School-Age: Does Maternal Asthma Modify the Effect?
Am J Respir Crit Care Med 2012; doi:10.1164/rccm.201108-1490OC. 

Narayanan M, Owers-Bradley J, Beardsmore CS, Madam M, Ball I, Garipov R, Panesar K, Kuehni CE, Spycher BD, Williams S, Silverman M.
Alveolarization continues during childhood and adolescence: new evidence from 3He magnetic resonance. 
Am J Respir Crit Care Med 2011; doi:10.1164/rccm.201107-1348OC

Conference abstracts

Dogaru C, Narayanan M, Strippoli MPF, Pescatore AM, Spycher BD, Beardsmore CS, Silverman M, Owers-Bradley J, Kuehni CE. 
Association between breastfeeding and lung volumes and alveolar size. 
European Respiratory Society annual congress, Amsterdam, 2011.

Narayanan M, Beardsmore CS,  Owers-Bradley J, Madam M, Garipov R, Ball I, Panesar K, Kuehni CE, Verbanck S, Silverman M. 
Evidence for acinar airway injury and alveolar catch-up growth in survivors of neonatal chronic lung disease. 
American Thoracic Society international congress, New-Orleans, 2010.

Narayanan M, Dogaru C, Panesar K, Beardsmore CS, Ball I, Mada M, Garipov R, Phillips J, Kuehni CE, Spycher BD, Silverman M, Owers-Bradley J. 
Early life parental smoking is associated with enlarged alveoli in later childhood: evidence from 3-helium magnetic resonance. 
European Respiratory Society annual congress, Barcelona, 2010.

Narayanan M, Dogaru C, Owers-Bradley J, Garipov R, Phillips J, Kuehni CE, Spycher BD, Silverman M, Beardsmore CS. 
Impact of parental smoking during early chidlhood on acinar airway inhomogeneity. 
European Respiratory Society annual congress, Barcelona, 2010.

Phillips J, Narayanan M, Owers-Bradley J, Garipov R, Wang JY, Kuehni CE, Spycher BD, Silverman M, Beardsmore CS. 
Conductive and acinar ventilation inhomogeneity by nitrogen washout in healthy children. 
European Respiratory Society annual congress, Barcelona, 2010.

Narayanan M, Owers-Bradley J, Ball I, Madam M, Kuehni CE, Spycher BD, Garipov R, Silverman M, Beardsmore CS. 
Evidence for continuous alveolarisation during childhood using 3He magnetic resonance. 
European Respiratory Society annual congress, Vienna, 2009.