The Truncated Splice Variant of the Granulocyte-Macrophage-Colony-Stimulating Factor Receptor β- Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns

Abstract

<b><i>Background:</i></b> The granulocyte-macrophage-colony-stimulating factor (GM-CSF) plays an important role in surfactant homeostasis. β<sub>C</sub> is a subunit of the GM-CSF receptor (GM-CSF-R), and its activation mediates surfactant catabolism in the lung. β<sub>IT</sub> is a physiological, truncated isoform of β<sub>C</sub> and is known to act as physiological inhibitor of β<sub>C</sub>. <b><i>Objective:</i></b> The aim of this study was to determine the ratio of β<sub>IT</sub> and β<sub>C</sub> in the peripheral blood of newborns and its association with the degree of respiratory failure at birth. <b><i>Methods:</i></b> We conducted a prospective cohort study in newborns with various degrees of respiratory impairment at birth. Respiratory status was assessed by a score ranging from no respiratory impairment (0) to invasive respiratory support (3). β<sub>IT</sub> and β<sub>C</sub> expression were determined in peripheral blood cells by real-time PCR. β<sub>IT</sub> expression, defined as the ratio of β<sub>IT</sub> and β<sub>C</sub>, was correlated with the respiratory score. <b><i>Results:</i></b> β<sub>IT</sub> expression was found in all 59 recruited newborns with a trend toward higher β<sub>IT</sub> in respiratory ill (score 2, 3) newborns than respiratory healthy newborns ([score 0, 1]; <i>p</i> = 0.066). Seriously ill newborns (score 3) had significantly higher β<sub>IT</sub> than healthy newborns ([score 0], <i>p</i> = 0.010). Healthy preterm infants had significantly higher β<sub>IT</sub> expression than healthy term infants (<i>p</i> = 0.019). <b><i>Conclusions:</i></b> β<sub>IT</sub> is expressed in newborns with higher expression in respiratory ill than respiratory healthy newborns. We hypothesize that β<sub>IT</sub> may have a protective effect in postnatal pulmonary adaptation acting as a physiological inhibitor of β<sub>C</sub> and, therefore, maintaining surfactant in respiratory ill newborns.

Commentary on the Truncated Splice Variant of the GM-CSF Receptor Beta-Chain in Peripheral Blood Serves as Severity Biomarker of Respiratory Failure in Newborns

“…After differentiation, AMs reside and self-perpetuate primarily from local progenitors in a process remarkably specific to the lung and GM-CSF. The present observations by Schulte et al [1] reveal that increased expression of GM-CSFRB (IT) RNA in neonates with respiratory illnesses raise the possibility that GM-CSFRV (IT) whether produced systemically, or within the alveolus, may influence AM activity, in turn modulating surfactant catabolism, pool size, and innate immunity. Thus, mechanisms controlling transcription, splicing, and accessibility of B (IT) peptide and the role of the B (IT) in control of AM or monocyte GM-CSF signaling are of considerable interest during the perinatal period, when postnatal surfactant homeostasis is established to enable pulmonary responses to physiologic and environmental challenges.…”

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In this issue, Schulte et al [1] report novel data demonstrating increased expression of GM-CSFR (IT) mRNA in peripheral blood cells of newborn infants with respiratory illness compared to those without respiratory signs and symptoms. Since GM-CSFR (IT) is a truncated receptor isoform that inhibits GM-CSF signaling in monocytes and macrophages, its expression may inhibit cellular processes dependent upon GM-CSF, including pulmonary surfactant catabolism and innate host defense in the lung.

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