Lysophosphatidic Acid Signaling through the Lysophosphatidic Acid-1 Receptor Is Required for Alveolarization

Abstract

Lysophosphatidic acid (LPA) signaling through one of its receptors, LPA 1 , contributes to both the development and the pathological remodeling after injury of many organs. Because we found previously that LPA-LPA 1 signaling contributes to pulmonary fibrosis, here we investigated whether this pathway is also involved in lung development. Quantitative assessment of lung architecture of LPA 1 -deficient knockout (KO) and wild-type (WT) mice at 3, 12, and 24 weeks of age using design-based stereology suggested the presence of an alveolarization defect in LPA 1 KO mice at 3 weeks, which persisted as alveolar numbers increased in WT mice into adulthood. Across the ages examined, the lungs of LPA 1 KO mice exhibited decreased alveolar numbers, septal tissue volumes, and surface areas, and increased volumes of the distal airspaces. Elastic fibers, critical to the development of alveolar septa, appeared less organized and condensed and more discontinuous in KO alveoli starting at P4. Tropoelastin messenger RNA expression was decreased in KO lungs, whereas expression of matrix metalloproteinases degrading elastic fibers was either decreased or unchanged. These results are consistent with the abnormal lung phenotype of LPA 1 KO mice, being attributable to reduced alveolar septal formation during development, rather than to increased septal destruction as occurs in the emphysema of chronic obstructive pulmonary disease. Peripheral septal fibroblasts and myofibroblasts, which direct septation in late alveolarization, demonstrated reduced production of tropoelastin and matrix metalloproteinases, and diminished LPA-induced migration, when isolated from LPA 1 KO mice. Taken together, our data suggest that LPA-LPA 1 signaling is critically required for septation during alveolarization.

Adult Lysophosphatidic Acid Receptor 1-Deficient Rats with Hyperoxia-Induced Neonatal Chronic Lung Disease Are Protected against Lipopolysaccharide-Induced Acute Lung Injury

“…We found that LPAR1-deficiency leads to alveolar enlargement or emphysema and decreased pulmonary vessel density in adult rats. This finding confirms observations in LPAR1 knockout mice showing that aberrant alveolar development caused by reduced secondary septation during early lung development was visible from 3 weeks after birth until adulthood (Funke et al, 2016 ). This explains why we did not observe alveolar enlargement in our previous study, in which the effects of LPAR1-deficiency on aberrant lung development were limited to the early neonatal period (Chen et al, 2016 ).…”

“…This explains why we did not observe alveolar enlargement in our previous study, in which the effects of LPAR1-deficiency on aberrant lung development were limited to the early neonatal period (Chen et al, 2016 ). LPAR1-deficiency may contribute to arrested alveolar development and reduced secondary septation by remodeling of elastic fibers, resulting in a reduction of disorganized septal fibers (Funke et al, 2016 ). The adverse effect of LPAR1 deficiency on alveolar development may limit the clinical usage of LPAR1 inhibitors for BPD.…”

Autotaxin in Pathophysiology and Pulmonary Fibrosis

“…Enpp2 has been suggested, using genome-wide linkage analysis coupled with expression profiling, as a candidate gene controlling lung function, development and remodeling ( 123 ). Accordingly, Enpp2 −/− mice were found to be embryonically lethal ( 46 – 48 , 78 ), while Lpar1 −/− mice were shown to have reduced alveolar septal formation during development ( 124 ). In adult life, ATX is constitutively expressed by bronchial epithelial cells, in both humans, and mice, and can be detected in BALFs ( 49 , 125 ).…”

<p>Inhibitors of the Autotaxin-Lysophosphatidic Acid Axis and Their Potential in the Treatment of Interstitial Lung Disease: Current Perspectives</p>

“… 44 Approximately 50% of LPAR1 null mice demonstrate perinatal lethality due to craniofacial defects and difficulties suckling, 45 whilst in contrast, heterozygous LPAR1 ± deficient mice survive postnatally but demonstrate phenotypic lung abnormalities with impaired pulmonary alveolarisation. 46 LPAR2 null mice have normal viability however and show no phenotypic abnormalities. 47 LPA 3 is essential for normal embryo implantation, as such, LPAR3 null mice demonstrate abnormalities in reproduction.…”

“… Funke et al 45 LPAR 1 ± heterozygous deficient mice Reduced alveolar septal formation. Contos et al 46 LPAR 2 -/- No phenotypic defect. Normal viability.…”