Submitted on March 7, 2007
Accepted on November 20, 2007
Ontogeny of the eotaxins in human lung
Kathleen J. Haley1*, Mary E Sunday2, Yolanda Porrata1, Colleen Kelley1, Anne Twomey3, Aliakbar Shahsafaei4, Benjamin Galper1, Larry A. Sonna5, and Craig M Lilly6
1 Pulmonary and Critical Care Division, Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, United States
2 Pathology, Brigham and Women's and Children's Hospitals, Boston, Massachusetts, United States; Pathology and Medicine, Duke University, Durham, North Carolina, United States
3 Department of Medicine, National Maternity Hospital, Dublin, Ireland
4 Pathology, Brigham and Women's Hospital, Boston, Massachusetts, United States
5 Division of Pulmonary and Critical Care, Department of Medicine, University of Maryland School of Medicine, Baltimore, Maryland, United States
6 Medicine, UMass, Worcester, Massachusetts, United States
* To whom correspondence should be addressed. E-mail: khaley{at}rics.bwh.harvard.edu.
The ontogeny of the C-C chemokines eotaxin-1, eotaxin-2, and eotaxin-3 has not been fully elucidated in human lung. We explored a possible role for eotaxin in developing lung by determining the ontogeny of eotaxin-1 (CCL11), eotaxin-2 (CCL 24), eotaxin-3 (CCL 26) and the eotaxin receptor, CCR3. We tested discarded surgical samples of developing human lung tissue using quantitative reverse transcription-polymerase chain reaction (QRT-PCR) and immunostaining for expression of CCL11, CCL24, CCL26 and the eotaxin receptor, CCR3. We assessed possible functionality of the eotaxin-CCR3 system by treating lung explant cultures with exogenous CCL11 and analyzing the cultures for evidence of changes in proliferation and activation of extracellular signal-related protein kinase-1/ 2 (ERK1/2), a signaling pathway associated with CCR3. QRT-PCR analyses of 22 developing lung tissue samples with gestational ages 10 to 23 weeks demonstrated that eotaxin-1 mRNA is most abundant in developing lung, whereas mRNAs for eotaxin-2 and eotaxin-3 are minimally detectable. CCL11 mRNA levels correlated with gestational age (P < 0.05), and immunoreactivity was localized predominantly to airway epithelial cells. QRT-PCR analysis detected CCR3 expression in 16 of 19 developing lung samples. Supporting functional capacity in the immature lung, CCL11 treatment of lung explant cultures resulted in significantly increased (P < 0.05) cell proliferation and activation of the ERK signaling pathway, which is downstream from CCR3, suggesting that proliferation was due to activation of CCR3 receptors by CCL11. We conclude that developing lung expresses the eotaxins and functional CCR3 receptor. CCL11 may promote airway epithelial proliferation in the developing lung.
