American Journal of Respiratory Cell and Molecular Biology

Bronchopulmonary dysplasia (BPD) is a debilitating disease in premature infants resulting from lung injury that disrupts alveolar and pulmonary vascular development. Despite the use of lung-protective ventilation and targeted oxygen therapy, BPD rates have not significantly changed over the last decade. Recent evidence suggests that sepsis and conditions initiating the systemic inflammatory response syndrome in preterm infants are key risk factors for BPD. However, the mechanisms by which sepsis-associated systemic inflammation and microbial dissemination program aberrant lung development are not fully understood. Progress has been made within the last 5 years with the inception of animal models allowing mechanistic investigations into neonatal acute lung injury and alveolar remodeling attributable to endotoxemia and necrotizing enterocolitis. These recent studies begin to unravel the pathophysiology of early endothelial immune activation via pattern recognition receptors such as Toll-like receptor 4 and disruption of critical lung developmental processes such as angiogenesis, extracellular matrix deposition, and ultimately alveologenesis. Here we review scientific evidence from preclinical models of neonatal sepsis-induced lung injury to new data emerging from clinical literature.

This review provides a mechanistic basis for the now decades-old observation that postnatal sepsis is associated with the development of bronchopulmonary dysplasia (BPD). This understanding will in turn foster increased recognition of those at risk of BPD, and translational approaches to preventing BPD pathogenesis following sepsis.

Preterm birth continues to be a significant contributor to the global burden of disease with approximately 15 million premature babies born annually (13). Bronchopulmonary dysplasia (BPD) is a source of long-term disability among premature infants, resulting in part from injury in the developing lung that disrupts alveolar and pulmonary vascular growth (4). Ventilator-induced lung injury, once thought to be the main culprit for BPD in preterm infants, is less common since the institution of gentler respiratory support strategies such as volume-targeted and noninvasive ventilation (5). However, the increase in disease incidence observed over the last decade among extremely premature infants adds significance to other BPD risk factors, such as postnatal infection, oxygen toxicity, fetal growth restriction, nutrition, and genetic makeup (69). Neonatal sepsis remains a significant cause of morbidity and mortality in premature infants, with the greatest risk coming with increasing degrees of prematurity (10). The incidence of sepsis within the first 72 hours of life (early-onset sepsis) is approximately 2–3.5% among infants born at less than 28 weeks’ gestation, whereas that of late-onset sepsis, occurring after 72 hours of age, ranges from 10% in infants of 29–32 weeks’ gestation to as high as 41% in those born after more than 25 weeks’ gestation (7, 10). Multiple clinical studies have demonstrated an increased risk of developing BPD following sepsis and other neonatal conditions with a similar systemic inflammatory response syndrome (SIRS), such as necrotizing enterocolitis (NEC) (1115), yet the pathophysiologic mechanisms by which neonatal sepsis and SIRS, particularly of late onset, impair lung development have just recently begun to be delineated. Here we review the existing scientific evidence linking postnatal sepsis and SIRS to the development of BPD.

Persistent neonatal lung inflammation has been demonstrated in association with several BPD risk factors (16), and systemic infections specifically produce lung inflammation through both direct stimulation of lung cells by microbial ligands as well as activated immune cells traveling through the pulmonary circulation. In an early investigation comparing the roles of postnatal sepsis and mechanical ventilation in the pathogenesis of BPD, Van Marter and colleagues studied 192 patients with birthweight of more than 1,500 g and found that postnatal sepsis alone (odds ratio [OR], 2.1; 95% confidence interval [CI], 1.4–3.1) raises the likelihood of developing BPD (11). Ohlin and colleagues (13) and Kim and colleagues (15) more recently described similar odds of developing moderate to severe BPD following postnatal or late-onset sepsis. The study by Kim and colleagues, a Korean neonatal network analysis of nearly 4,000 extremely premature infants accounting for several confounders, also found that the strength of that association did not depend on gestational age under 28 weeks (15). There is inconsistency in the above studies, however, in handling neonates with culture-negative sepsis, defined as clinical deterioration and full antibiotic treatment course without blood culture growth. Ohlin and colleagues notably found that culture-negative sepsis did not correlate with the development of BPD (adjusted OR, 1.1; 95% CI, 0.6–2.0) when analyzed separately (13), and further investigation is merited to determine whether this population of ill neonates truly is at risk or conversely deserves exclusion. Since coagulase-negative Staphylococcus (CoNS) is the most common organism causing late-onset neonatal sepsis at present, Liljedahl and colleagues compared the incidence of BPD among preterm infants (<30 weeks’ gestation) with CoNS infection and found that infants with CoNS sepsis also had the highest incidence of BPD at 64%, followed by those with other sources of sepsis at 41%, whereas 24% of infants without sepsis developed BPD (12). Importantly, reductions in neonatal sepsis correlate to a lower incidence of BPD, as was borne out in a large retrospective population-based cohort study by Lapcharoensap and colleagues, which saw the incidence of neonatal intensive care unit infections in California decrease from 24.7 to 15% over a 7-year period whereas the incidence of BPD decreased from 35% to 30% during the same time frame (17). Current literature thus supports the hypothesis that postnatal sepsis increases the risk of BPD in premature infants.

In adults and older children, sepsis is a common and severe cause of acute lung injury (ALI), resulting in higher mortality and an increased number of intensive care admissions compared with other etiologies of ALI (18, 19). Although sepsis-induced ALI has not been directly studied in premature infants, several investigations demonstrate that neonatal sepsis is associated with the elevation of systemic proinflammatory cytokines shown experimentally to mediate indirect ALI, including IL-6, IL-1β, IFN-γ, and TNF-α (2023). Although many of these cases arise from bacterial bloodstream infections with Escherichia coli, group B Streptococcus (GBS), Staphylococcus spp., and others, fungemia with Candida spp. (24), and viremia with Cytomegalovirus (CMV) (25) are additional causes of postnatal lung injury in premature newborns. It is also not difficult to extrapolate this pathogenic mechanism of lung injury to patients with NEC, a severe intestinal inflammatory disease where gut integrity is compromised, translocation of enteric bacteria is anticipated, and SIRS ensues. Studies of septic neonates with culture-proven infection often include those with moderate to severe NEC as a pathogenic source (21, 22). And although a bloodstream microbe is not always isolated in cases of NEC, the profile and magnitude of elevation of systemic cytokines in this condition mimics that of infants with culture-proven sepsis from other sources (22, 26). The systemic elevation in inflammatory cytokines observed in neonates with NEC substantiates the findings of clinical studies that have shown an increased future incidence of BPD in these patients (27, 28). More specifically, a multicenter study using data from the Spanish Neonatal Network by Zozaya and colleagues showed that the incidence of BPD increased significantly between premature infants without NEC compared with infants with nonsurgical NEC (OR, 1.44; 95% CI, 1.18–1.77) and those with surgically treated NEC (OR, 2; 95% CI, 1.71–2.33) (29). An analysis by Leviton and colleagues further observed that extremely premature newborns with NEC had a higher risk of BPD than those with sepsis (culture-proven or suspected), though the source of infection was not specified (27). In sum, clinical experience has found that premature infants whose early clinical course is complicated by sepsis and NEC are especially prone to develop BPD. Data from experimental animal models of neonatal sepsis have started to fill in the mechanistic gaps in this relationship.

Traditionally, most preclinical models of BPD exposed animals to hyperoxia with or without pre- or perinatal LPS to mimic oxygen toxicity and chorioamnionitis-induced alveolar simplification in BPD. It is only recently that mechanistic studies to elucidate the pathogenesis of postnatal sepsis-induced BPD have been modeled in animals. These in vivo studies typically treat newborn mice with sublethal doses of systemic LPS or endotoxin, the major cell wall component of gram-negative bacteria that triggers the sepsis cascade upon recognition by the Toll-like receptor (TLR) family of innate immune receptors (30, 31). This sterile stimulus induces systemic inflammation, but importantly also recapitulates the pulmonary endothelial barrier disruption and lung neutrophilic influx well-characterized in adult and pediatric sepsis-induced acute respiratory distress syndrome (ARDS) and ALI (18, 19, 32). Investigations employing postnatal, systemic LPS have timed the insult to the saccular stage of lung development, typically between Postnatal Day 0 and 5 in mice (33), correlating to when hospitalized extremely premature human neonates are most susceptible to SIRS from sepsis or NEC. This ontogenic window is vulnerable to inflammation-induced disruption of lung morphogenic pathways critical for distal acinar development. LPS-based neonatal animal studies have thus yielded insight into several mediators of alveolar and pulmonary vascular development, though in many of these models, lung morphologic abnormalities resolve by postnatal Day 21 to 28 (P21–P28). Although many investigations have used GBS (3438) or CMV (39, 40) infection to induce lung injury in neonatal animal models, observations of lung developmental outcomes are limited in these studies. Efforts have also been made to reproduce polymicrobial, gut-derived sepsis through mouse models of intestinal inflammation (23, 41) and cecal slurry injection (42), though again long-term observations are lacking as survival is limited.

In 2014, the European Society for Pediatric and Neonatal Intensive Care published the Montreux definition for neonatal ARDS (32), formally recognizing a clinical syndrome of hypoxemic respiratory failure distinct from the respiratory distress syndrome seen with primary surfactant deficiency in premature newborns. The pathophysiology of sepsis-induced indirect lung injury has been extensively characterized in adult human and animal studies of ALI and ARDS (18, 19), and more recent investigations have shed light on mechanisms by which the neonatal lung is acutely injured during sepsis. Neonates share many features of sepsis-induced ALI in common with older children and adults, such as increased vascular permeability, inflammation, and cell death. However, the premature newborn lung is vulnerable to developmental arrest during both the acute and convalescent phases of injury, portending the development of BPD.

The innate immune recognition of microbial pathogen-associated molecular patterns, such as LPS, by endogenous pattern recognition receptors, such as TLRs and C-type lectin receptors, initiates a host inflammatory response in both adults and neonates with sepsis (43, 44). Genetic variance of TLRs in neonates in fact influences susceptibility to bacterial infection and the inflammatory response (45). Pathogen-associated molecular patterns and cytokines including LPS (44), IL-1β (46), IL-6 (23), IFN-γ (47), and cold-inducible RNA-binding protein (42) induce pulmonary endothelial cell (EC) immune activation. The loss of EC quiescence results in the recruitment and activation of neutrophils and macrophages (32), production of reactive oxygen species (ROS) (48), endothelial and alveolar epithelial cell death by apoptosis (49), and microvascular thrombosis (50), all promoting lung injury in the neonate. Loss of alveolar-capillary barrier integrity, the hallmark of ALI and ARDS, occurs via stimulation of the actin-myosin cytoskeleton and stress fiber formation by aberrant angiogenic growth factor signaling and other inflammatory mediators (47), allowing the alveolar influx of inflammatory cells and a protein-rich edema fluid previously demonstrated by BAL of neonates with ALI (46, 51, 52). Diffuse alveolar damage, typical in ARDS, has also been observed during the saccular and early alveolar stages of neonates with sepsis (53). Some cell signaling pathways activated to restore damaged lung architecture are shared with developmental pathways, including those regulated by transforming growth factor-β (TGF-β, 54), fibroblast growth factors (54), and Wnt (55), but deviation from cell-type specificity and spatiotemporal patterning can disrupt alveologenesis. Taken together, these diverse yet interwoven facets of ALI and ARDS form a foundation for understanding how the neonate with sepsis develops BPD.

Here we explore the seminal findings of basic and translational studies investigating the role of postnatal sepsis and inflammation in lung development (Figure 1). Preclinical investigations into the mechanisms by which chorioamnionitis, hyperoxia, and mechanical ventilation contribute to BPD, alone or in combination with postnatal endotoxin exposure, have previously been reviewed by others in several excellent articles (5660).

Pulmonary Endothelium and Vascular Development

Stunted pulmonary vascular growth and dysmorphic microvascular arborization contribute to impaired alveologenesis and pulmonary hypertension in BPD (61). Lung EC dysfunction is a hallmark of sepsis-induced ALI and in preterm infants can lead to structural alterations in vascular development. In rodent models of postnatal systemic LPS-induced lung inflammation, acute EC injury results in a reduced number and density of pulmonary vessels during alveologenesis (62, 63). Shrestha and colleagues noted that this systemic LPS-induced “pulmonary vascular simplification” was dose-dependent and more prominent with LPS treatment during the saccular but not the alveolar stage, whereas alveologenesis was impaired at both stages (63). In a subsequent study, Shrestha and colleagues found that the combination of LPS and hyperoxia is required to significantly increase pulmonary arterial pressure and muscularization, features of pulmonary hypertension, whereas hyperoxia alone did not induce these changes (64). Choi and colleagues observed morphometrically that postnatal LPS affected vascular density proportionately more than vessel number in neonatal rats, suggesting a deficit in angiogenesis in addition to vasculogenesis, though this difference was not specifically tested for (62). In vitro, several studies using isolated human lung EC or mouse lung EC have shown that bacterial ligands can directly induce dysmorphic angiogenesis in a cell-autonomous manner (6567).

As mediators of both developmental angiogenesis and sepsis-induced dysmorphic angiogenesis, vascular growth factors have a complex role in sepsis-driven BPD. Although Choi and colleagues observed a paucity of pulmonary blood vessels following LPS in neonatal rats, lung vascular endothelial growth factor (VEGF) and hypoxia inducible factor 1-α gene expressions were elevated up to 7 days after exposure (62). In fetal human pulmonary microvascular EC, our group observed that VEGF transcript concentrations peak 7 hours after LPS exposure and that this rise is necessary for aberrant angiogenesis induced by LPS (67). VEGF is a well-characterized mediator of inflammation and endothelial barrier disruption in adult sepsis (18), and Syed and colleagues showed that lung-specific VEGF overexpression from P1 to P7 induced acute pulmonary vascular leak and lung injury, leading to abnormal pulmonary vascularization and alveolar simplification at P14 (68). Although this study did not directly investigate neonatal sepsis, these data suggest that the persistent induction of VEGF, as seen during sepsis, can mediate ALI and potentially BPD (68). Constitutive signaling of angiopoietin 1 via the Tie2 receptor antagonizes the proinflammatory effects of VEGF, and our group showed both in human pulmonary microvascular EC and murine lungs that recombinant angiopoietin 1 preserves Tie2 activation, maintains endothelial quiescence, and inhibits ALI after endotoxin exposure (69). Although VEGF and angiopoietins have been implicated in sepsis-induced EC dysfunction before, we used an unbiased discovery approach to identify FOS-like 1 (FOSL1) as a novel transcriptional regulator of LPS-induced deviant angiogenesis in neonatal mice (66). LPS activated FOSL1 and caused deviant angiogenic tube formation concurrently with the upregulation of EC genes previously implicated in pathological angiogenesis, specifically ADAM8, CXCR2, HPX, LRG1, PROK2, and RNF213 (66).

Several investigators have begun to uncover novel crosstalk between pulmonary endothelial immune pathways and angiogenic/vasculogenic factors, supporting the concept of lung EC as conditional immune cells (70). ROS and diminished antioxidant enzyme capacity have long been implicated as mediators of endotoxin’s effects during sepsis in several cell types, and Menden and colleagues demonstrated that lung EC nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) mediates TLR4-mediated MAP kinase and NF-κB activation, leading to ALI and alveolar simplification (71). Shrestha and colleagues showed that systemic LPS also impairs the expected antioxidant enzyme responses of NQO1 and HO-1 to oxygen exposure in neonatal mice, resulting in severe pulmonary vascular remodeling and worse alveolar remodeling (63). Histone deacetylase 6 (HDAC6), which acts both in the cytoplasm and nucleus, represses EC immune activation by deacetylating MYD88 and NF-κB. HDAC6 inhibition thus led to exaggerated LPS-induced TLR4 signaling, ALI, and alveolar simplification in neonatal mice (72). Xia and colleagues recently identified forkhead box protein C2 (FOXC2), a transcription factor known previously in lymphatic EC lineage specification, as an additional regulator of EC TLR4 responsiveness (73). Exposure to LPS induced FOXC2 and its downstream target delta-like 4, an EC Notch ligand, both in murine and human lung EC, to mediate dysmorphic angiogenesis (73). This study provides a direct link between a vascular transcription factor implicated in EC developmental programming and EC immune activation. In a more recent study, Xia and colleagues demonstrate that in the setting of LPS-induced inflammation, pulmonary endothelial FOXC2 autoregulates its expression by binding to its own promoter, potentially perpetuating a cycle of aberrant angiogenesis in the developing lung (74). With GBS, Gibson and colleaues found that this pathogen has a predilection to invade and injure lung microvascular endothelial cells during infection (34), also inducing endothelial immune activation via nitric oxide (NO) and prostaglandin E2 (35, 36). Further elucidation of the crosstalk between lung EC immune signaling and vascular developmental pathways in the context of bacteria that stimulate TLR2 or NOD-like receptors will also provide mechanistic insight on deviant EC/vascular signaling in sepsis-induced BPD.

Epithelial Cell Injury and Reprogramming

The induction of proinflammatory pathways in alveolar epithelial cells during neonatal sepsis can disrupt developmental programs critical for alveologenesis, skewing toward abnormal alveolar development and BPD. LPS-exposed newborn mice display acute and chronic decreases in pulmonary gene expression and protein concentrations of FGF2, FGF7, and the FGF receptor 1 (FGFR1), all important for branching morphogenesis and alveolar epithelial cell function (64, 71, 72). Shrestha and colleagues further demonstrated that the decrease in epithelial FGFR1 was dependent on the dose of LPS used (63). Lung proteomic data from Shrestha and colleagues also showed that β-catenin is downregulated in LPS-exposed neonatal mice (63), implicating disrupted β-catenin/Wnt signaling as another potential mechanism underlying disrupted alveolar epithelial cell development and alveologenesis. Finally, exosomes and exosomal microRNAs (miRNAs) have emerged as regulators of cell differentiation and organ development, and Lal and colleagues observed that exosomal miRNA876–3p specifically is decreased in the airways of extremely premature infants who proceed to develop severe BPD (75). LPS or E. coli exposure downregulate exosomal miRNA876–3p in human airway epithelial cells in vitro, and the magnitude of this downregulation is greater than in the presence of hyperoxia, implying that sepsis-induced inflammation alone is a key stimulus for epithelial miRNA dysregulation (75). The potential role of exosomal miRNAs in mediating pulmonary epithelial injury versus development in animal models of sepsis-induced lung injury remains an opportunity for further investigation.

Similar to lung EC, the pulmonary epithelium can take on a proinflammatory state in response to neonatal sepsis and SIRS. In a murine model of NEC, Jia and colleagues showed that TLR4 mRNA is upregulated in the lung (41). Using transgenic mice specifically expressing TLR4 in the intestine, lung, or both, Jia and colleagues further demonstrated that the receptor’s presence in the pulmonary epithelium is requisite for lung injury during NEC (41). In a GBS in vitro model, Doran and colleagues showed in vitro that the virulence factor β-hemolysin enables bacterial invasion and immune activation of lung epithelial cells, particularly in the setting of surfactant deficiency (47). In an in vitro study of isolated neonatal piglet type II alveolar epithelial cells (AT2), He and colleagues found that LPS-induced cytokine gene expression correlated temporally with decreased gene expression of surfactant proteins A, B, and C, increased apoptosis, and decreased proliferation (76). This LPS-induced AT2 cell pathology was rescued in a dose-dependent fashion by dexamethasone, presenting mechanistic evidence of the potential for corticosteroids to improve lung development following neonatal bacterial sepsis (76). Mice genetically modified for lung epithelial overexpression of inflammatory mediators provide an additional tool to study the influence of sepsis on lung development. In a transgenic mouse model of lung-specific IL-1β overexpression, Hogmalm and colleagues observed alveolar simplification at P14 in conjunction with a decrease in club cell secretory protein (CCSP)-expressing cells (77), a population critical to airway regeneration. These investigators also found that goblet cells were increased, hyperplastic, and had higher expression of CLCA3, a protein that promotes mucus metaplasia (77).

It should be noted that epithelial-mesenchymal transition (EMT), a key pathologic driver of BPD-associated lung fibrotic change, has yet to be examined in detail in experimental models of neonatal sepsis-induced BPD. In LPS-based lung developmental models, prolonged elevation of TGF-β (76, our lab’s unpublished results) offers some evidence that lung fibrotic change may follow neonatal sepsis. Thus, further characterization of systemic LPS-mediated changes in TGF-β signaling would be a welcomed addition to literature defining the relationship between sepsis, EMT, and BPD.

The Mesenchyme, Extracellular Matrix, and Fibroblasts

Alveologenesis requires highly coordinated processes in the lung mesenchyme, including the deposition, breakdown, and reformation of elastic and collagen fibers performed by myofibroblasts and lipofibroblasts, all of which are vulnerable to disruption by sepsis-derived inflammation (78, 79). This pathology in part involves active protease-mediated lung ECM degradation, which has consistently been demonstrated in adult models of sepsis-induced lung injury (54, 80, 81). In neonatal mice systemically exposed to LPS at P6, we have observed elevation of matrix metalloproteinase-9 relative to tissue inhibitor of matrix metalloproteinase-1 and elastic fiber breaks acutely, well before alveolar simplification is observed (69, 71). In parallel with tissue destruction, downregulation of crucial mesenchymal and fibroblast growth factors has also been demonstrated in mouse models of sepsis-induced BPD, including FGFR1, FGF2, FGF7, and β-catenin (63, 71).

Lung elastic fiber assembly and organization has been shown to be aberrant in experimental neonatal sepsis. Following murine LPS-induced neonatal lung injury, elastic fibers surrounding terminal airspaces in saccular lungs were found to be thin, disjointed, or absent (72), correlating to similar observations in preterm human infants exposed to systemic inflammation (82). Benjamin and colleagues further explored the interaction between inflammation and neonatal elastic fiber disorganization, finding that chronic lung inflammation in saccular-stage mice triggered by inducible lung-specific NF-κB downregulated the key elastic fiber assembly components elastin and fibulin 5, in conjunction with a failure of alveologenesis (82). In saccular stage (P2) mouse primary fibroblasts exposed to LPS, fibulin-5 reconstitution rescued fibroblast elastin assembly (82). In a more recent study using the same lung epithelial NF-κB-inducible mouse line, Benjamin and colleagues describe a role for neutrophil elastase in inhibiting elastic fiber assembly, in part via the downregulation of fibroblast TGF-β (83). The extension of these studies to an in vivo model of postnatal sepsis-induced inflammation would yield important insights into the role of lung resident fibroblasts and elastic fiber assembly in sepsis-induced BPD.

Hematopoietic and Immune Cells

The proinflammatory activity of neutrophils is an important driver of sepsis-induced lung injury, and prolonged alveolar neutrophil influx, neutrophil elastase activity, and neutrophil myeloperoxidase activity have been shown in neonatal murine models of sepsis or inflammation-induced alveolar simplification (63, 72, 82, 83), similar to human neonates who develop BPD (84). The implications of neutrophil inhibition during neonatal sepsis were investigated in the aforementioned inducible lung-specific NF-κB overexpressing mouse line by Benjamin and colleagues, who found that neutrophil depletion by anti-Ly6G antibody administration during saccular stage lung inflammation rescued alveologenesis (83). The extension of anti-neutrophil strategies to in vivo neonatal LPS-induced lung injury models will be an important future step to determine whether this is a viable strategy to prevent BPD following newborn sepsis.

Macrophage inflammasome activation, signified by the production of IL-1β, is well-described in septic neonates. Hogmalm and colleagues used transgenic IL-1β-overexpressing neonatal mice to demonstrate that dysregulated inflammasome activity can directly contribute to pathologic alveolar remodeling via chronic inflammation (77). In a study with potential therapeutic implications, Mckenna and colleagues showed that LPS-induced IL-1β upregulation can be blocked by inhibiting IKKβ/NF-κB signaling in cultured macrophages while also preserving beneficial NF-κB-mediated anti-apoptotic gene expression (85). Importantly, these findings were replicated in LPS-exposed neonatal mice (85), though whether decreased IL-1β expression improved alveologenesis in this setting was not examined. Given the recent promise of IL-1 receptor antagonism to treat neonatal sepsis-induced lung injury and alveolar maldevelopment in preclinical models, Butler and colleagues investigated the neonatal regulation of IL-1α, a cytokine relatively understudied in the developing lung (86). LPS-exposed newborn mice and airway macrophages had robust induction of IL-1α regulated by the innate immune response, specifically NF-κB (86). Importantly, LPS-induced IL-1α expression was specific to the lung and to saccular-stage (P0) mice, as opposed to their alveolar stage (P7 or P28) or adult counterparts, meriting further scrutiny of IL-1α function in the developing lung (86).

In evaluation of alveolar macrophages, Lund and colleagues revealed a developmental immaturity of this cell type in neonates signified by low expression of the lectin SIGLEC-1 receptor (38). Functionally, this immaturity contributed to poor killing and clearance of GBS in mice, resulting in more severe lung injury. In studies of postnatal CMV viremia in mouse pups, Stahl and colleagues revealed a tropism of this pathogen to alveolar macrophages (39). Within macrophages, CMV facilitated formation of nodular inflammatory foci, a previously described pathogenic mechanism in CMV pneumonitis leading to viral replication and persistent inflammation (40). Further characterization of alveolar macrophage reprogramming and potential lung developmental sequelae would be a welcomed addition to the investigations described above. A thorough understanding of the development of other lung resident immune cells is also lacking in studies of neonatal sepsis and BPD. Shrestha and colleagues showed that postnatal systemic LPS exposure decreases pulmonary T regulatory cells in neonatal mice, suggesting a more limited ability to suppress future inflammatory insults (63). Structurally, Hogmalm and colleagues demonstrated an increase in B- and T-cell follicles in neonatal mice with pulmonary IL-1β overexpression (77). However, the implications of these and other alterations of lung resident immune cells for alveolar development are unclear and a ripe area for future study.

Neonatal sepsis and NEC-induced SIRS have emerged as risk factors for BPD (87). From the clinical perspective, further refinement and dissemination of a clinical definition for neonatal ALI/ARDS, using a combination of lung/systemic biomarkers and lung injury indices such as the pulmonary severity score, will aid neonatologists in identifying those infants with confirmed or suspected sepsis most at risk of BPD. The application of genomics, transcriptomics, and proteomics, or lar to detect markers of lung injury in the peripheral circulation will also help in this regard, as it has in patients with viral bronchiolitis (88). Ultimately, understanding whether there is a specific subset of patients with BPD marked by early sepsis will enable a precision medicine-based approach to their treatment.

Animal models have begun to distinguish the mechanisms underlying sepsis-induced injury of lung developmental pathways from hyperoxia and other sources of neonatal lung injury. The prominent role of lung EC immune activation in acute lung inflammation and the upregulation of transcriptional controllers that promote deviant EC fate and dysmorphic lung vascularization, e.g., FOXC2 and FOSL1, is recognized. Bacterial ligands also disrupt the FGF and β-catenin/Wnt pathways regulating morphogenesis in alveolar epithelial cells. In addition, sepsis mediators disrupt assembly of the alveolar elastic fiber network while also degrading this critical scaffold for the developing lung. Several gaps in our understanding of sepsis’ impact on alveologenesis and lung vascularization remain, however. Many canonical pathways and cell types involved in lung development have yet to be studied in the context of sepsis-induced lung injury, such as myo- and lipofibroblast differentiation and TGF-β signaling. In addition, using inocula of live bacteria in animal models will be essential to advance antiinflammatory treatments.

Therapeutically, a focused approach to quelling ALI in a cell compartment-specific manner will be an important adjunct to antibiotics and infection source control in septic neonates. Dampening lung EC immune activation early during sepsis may be especially productive, and nanoparticles administered in the bloodstream offer a means to target pharmacologic therapy to the pulmonary endothelium. Neutrophil elastase and metalloproteinase inhibition have shown promise in preserving elastic fiber deposition and alveologenesis in preclinical studies of neonatal ventilator-induced lung injury (89) and merit investigation in sepsis models. Although IL-1 receptor antagonism with medications such as anakinra could dampen the harmful effects of IL-1β on lung development, timing, duration, and patient selection need to be defined. Lastly, mesenchymal stem/stromal cells and mesenchymal stem/stromal cell-derived exosomes have multidimensional effects in attenuating inflammation and tissue destruction while also aiding in reparative responses, and they may serve as adjunctive therapies to prevent neonatal sepsis-induced ALI and BPD (90, 91).

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Correspondence and requests for reprints should be addressed to Venkatesh Sampath, M.D., Professor of Pediatrics, Sosland Chair in Neonatal Research, 2401 Gillham Road, Division of Neonatology, Kansas City, MO 64108. E-mail: .

Supported by National Heart, Lung, and Blood Institute grant 1R01 HL128374-05 and Eunice Kennedy Shriver National Institute of Child Health and Human Development grant 1R01 HD104215-01 (V.S.).

Author Contributions: U.S. and V.S. conceived the manuscript. K.D. and M.H.T. contributed to the section on clinical evidence. C.S.D.C. contributed to the section on acute lung injury pathophysiology. U.S. drafted the manuscript. All authors reviewed and edited the manuscript prior to submission.

Originally Published in Press as DOI: 10.1165/rcmb.2021-0353PS on October 13, 2021

Author disclosures are available with the text of this article at www.atsjournals.org.

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