Altered expression of key growth factors (TGFα, TGFβ 1 , PDGF‐A) and flawed formation of alveoli and elastin (Eln) in lungs of preterm (PT) lambs with chronic lung disease (CLD)

Abstract

Mechanical ventilation (MV) with O2-rich gas for 3 wks leads to CLD in PT lambs, as it does in PT infants. Reduced numbers of enlarged airspaces and excess, disordered lung Eln are key features of CLD. Studies in mice show that modified expression of specific growth factors (overexpressed TGFα or TGFβ1; deleted PDGF-A) and of genes that impact Eln assembly (deleted fibulin 5, fbn 5, or lysyl oxidase-like 1, LOXL 1) yield lung defects resembling CLD. Our goal was to define changes in gene expression of key growth factors and proteins that regulate Eln assembly in lungs of PT lambs with evolving CLD. We used quantitative RT-PCR to measure mRNA for TGFα, TGFβ1, PDGF-A, and Eln-related genes (tropoelastin, TE; lysyl oxidase, LOX; fibrillin 1, fib 1; fbn 5; LOXL 1) in lungs of PT lambs that received MV with O2 for 1 d, 3 d or 3 wks. Controls included PT fetal lungs and unventilated lungs of term lambs (same post-conception age as PT lambs that had MV for 3 wks). Lung mRNA for TGFα and TGFβ1 was 2- to 3-fold greater in PT lambs given MV for 1 d compared to control fetuses. PDGF-A mRNA decreased to <50% of fetal control values after 3 wks of MV. Fbn 5 mRNA did not change during 3 wks of MV (in contrast to increased lung mRNA of TE, LOX, fib 1, LOXL 1). We conclude that early postnatal increases in lung TGFα and TGFβ1, which can impact Eln fiber formation, coupled with later reduction in lung PDGF-A, which directs septal localization of Eln, could induce abnormal alveolarization in lambs with CLD. Increased lung expression of genes that regulate Eln synthesis and assembly, with no increase in fbn 5 mRNA, could impair lung Eln assembly in lambs with CLD. Funded by NIH RO1 HL62512, P50 HL56401