LAUSR

Bronchopulmonary dysplasia (BPD) is the most commonmorbidity associated with preterm birth, affecting up to 50–60% of babies born with birth weights less than 1,000 grams when the lungs are at the saccular stage of development (1). Themultifactorial pathogenesis of BPD is governed by a complex interplay between various antenatal and postnatal exposures and immature lung tissue. At the molecular degree, these interactions trigger an inflammatory response and ultimately result in the characteristic pathology of BPD: disrupted alveolarization and vascularization with variable degrees of fibrosis (2). Patients with severe BPD continue to require invasive or noninvasive ventilatory support when they reach term age and are at high risk of developing yet another potentially lethal complication: pulmonary arterial hypertension (3, 4). As the clinicians are pushing the envelope on the limits of viability, we are likely to see an increasing number of infants with severe BPD and pulmonary arterial hypertension. Hence, there is an urgent need for a better understanding of the molecular mechanisms underlying these disorders for the development of safe and efficient therapies, which are still lacking. In this issue of the Journal, Bonafiglia and colleagues (pp. 562–573) from the Bendeck Laboratory report their findings on cardiovascular and pulmonary effects of DDR1 (discoidin domain receptor 1) deficiency in mice (5). DDRs are unique receptor tyrosine kinases that are activated by collagens (6, 7). In vitro experiments have demonstrated that phosphorylated DDR1 activates intracellular signal transduction pathways that regulate cell migration and differentiation and matrix metalloproteinase expression (8, 9).Ddr1deficient (Ddr1) mice, which were generated more than 2 decades ago, have provided additional important insights into the biological role of DDR1 (10). These mice exhibit normal embryonic development, but homozygous females display defects in implantation and lactation. DDR1 is overexpressed in lung samples from patients with idiopathic pulmonary fibrosis, andDdr1 mice are resistant to bleomycin-induced pulmonary fibrosis and inflammation (11). As a result of carefully conducted, comprehensive studies by Bonafiglia and colleagues, we now have become aware of new phenotypic features associated with DDR1 deficiency, which include impaired alveolarization and PH. These findings, to a large extent, help explain the increased mortality observed inDdr1 mice between 1 and 4months of age. A combination of hemodynamic measurements obtained by right ventricle catheterization and echocardiograms and histologic analyses demonstrated elevated right ventricle systolic pressures, right ventricle hypertrophy and systolic dysfunction, right atrial enlargement, and increased number of muscularized distal arteries, all consistent with a diagnosis of pulmonary arterial hypertension, in 1-month-oldDdr1 mice. Although these cardiac anomalies were absent in younger mice at postnatal Day (P)7,Ddr1 pups displayed increased muscularization of distal pulmonary arteries compared with wildtype mice at this time point, thus revealing a plausible time course and pathogenesis for the development of pulmonary arterial hypertension. Furthermore,Ddr1 mice demonstrated fewer and larger alveoli, akin to the classic BPD pathology, and reduced body weight at P7. However, in contrast to the human and other murine models of BPD, these structural alterations were not associated with increased inflammation at P7 inDdr1 mice. How does DDR1 deficiency impair alveolarization and cause pulmonary arterial hypertension? Do these two pathologic processes occur through independent actions of DDR1 on the developing air saccules and distal pulmonary arteries, or are they linked to each other as that occurs in human infants with BPD? To begin to answer these mechanistic questions, knowledge of the cell types which express Ddr1 in murine lungs is a prerequisite. In the normal human lung, Moll and colleagues have reported that DDR1 is expressed in epithelial cells lining the airways and the alveoli by immunohistochemistry using a well-characterized anti-human DDR1 antibody (12). These immunolocalization studies are corroborated by recent single-cell RNA sequencing, which has detectedDDR1 transcripts in fibroblasts in addition to epithelial cells in the human lung (13). Unfortunately, the lack of a commercially available antimouse Ddr1 antibody has precluded Bonafiglia and colleagues from examining the expression of Ddr1 in murine tissues. However, based on single-cell RNA sequencing from the LungMap project, Ddr1 expression is detected in fibroblasts, endothelial cells, airway epithelial cells, and CD163macrophages in murine lungs (13). These data combined with the studies conducted in A549 cells, albeit not primary alveolar epithelial cell cultures, and decreased number of proliferating nuclear cell antigen (PCNA)-positive alveolar epithelial cells strongly suggest impaired alveolar epithelial cell proliferation andmigration as the underpinnings of alveolar simplification observed inDdr1 mice. Furthermore, from amechanistic standpoint, the authors propose an interesting concept of “partial” epithelial to mesenchymal transition (EMT) as a requirement for alveolarization to link their finding of decreased markers of EMT to impaired alveolarization inDdr1 mice. Although the contribution of decreased EMT to DDR1-mediated antifibrotic effects is well recognized, the notion of decreased EMT during alveologenesis would require further experimental evidence. In conclusion, while it is tempting to attribute the pulmonary vascular and cardiac pathology inDdr1 mice to alveolar simplification as that occurs in BPD, the finding ofDdr1expression in other cell types besides alveolar epithelial cells raises the possibility that