Maternal smoking, particularly during pregnancy, is a risk factor for early childhood wheezing and/or asthma. Little is known about the mechanisms that link maternal smoking and abnormal lung development and/or function. However, smoking is known to alter cytokine expression in smokers, and several mediators with proinflammatory actions in adults function as growth factors during development. We propose that the link between maternal smoking and postnatal lung dysfunction is an alteration in the expression of mediators affecting pulmonary organogenesis. Our central hypothesis is that maternal tobacco smoking increases the expression of proinflammatory mediators that act as growth factors in the lung during gestation. Although many mediators are probably affected by maternal smoking, we will focus on one proinflammatory chemokine, eotaxin, as a paradigm for effects of maternal smoking on lung development. While eotaxin is associated with adult asthma, the function of eotaxin in the developing lung is not known. We will use eotaxin as a candidate mediator to test our central hypothesis, addressing three specific aims.
The first aim i s to confirm that eotaxin and its receptor, CCR3, are expressed in specific temporal and anatomic patterns within the developing lung, and that these patterns differ between lungs exposed to tobacco smoke byproducts and lungs without such exposure.
The second aim i s to determine whether activation of transcription factors is the mechanism of the increased expression of eotaxin, a chemokine that has been shown to be transcriptionally regulated, in lungs exposed to tobacco byproducts.
The third aim i s to investigate whether maternal smoking alters lung growth and/or differentiation through an eotaxin-responsive mechanism.
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