Krithika Lingappan

Verified

University of Pennsylvania · Rehabilitation Medicine

Active 2006–2026

h-index30

Citations3.6k

Papers15681 last 5y

Funding$5.7M1 active

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About

Krithika Lingappan, MBBS, PhD, MS, is an Associate Professor of Pediatrics specializing in Neonatology and Newborn Services at the Children's Hospital of Philadelphia. She is also a faculty member at the Lung Biology Institute, Cardiovascular Institute, Institute of Translational Medicine and Therapeutics, and the Center for Excellence in Environmental Toxicology at the University of Pennsylvania. Her clinical expertise focuses on evidence-based medicine and translational research related to long-term outcomes such as pulmonary and cardiovascular health after preterm birth. She has leadership experience at national and regional organizations, including involvement in the American Academy of Pediatrics and NIH-funded lung basic-science research. Her research aims to reduce long-term morbidities like chronic lung disease (bronchopulmonary dysplasia) in premature infants, with a focus on understanding sex-specific differences in BPD incidence to develop therapeutic lung-protective strategies. Her long-term goal is to develop translational diagnostic and therapeutic strategies to improve neonatal lung injury outcomes.

Research topics

Medicine
Biology
Internal medicine
Immunology
Physiology

Selected publications

The importance of sex as a biological variable in pulmonary vascular research
American Journal of Physiology-Lung Cellular and Molecular Physiology · 2026-05-01
article
Sex differences shape disease susceptibility, progression, and therapeutic response across human health, yet their systematic integration into biomedical research remains uneven. In preclinical studies, animals of only one sex are frequently used, the sex of primary cells is often unreported or inconsistently documented, and experiments are rarely powered or analyzed to detect sex-specific effects. These limitations are particularly consequential in pulmonary arterial hypertension (PAH), a disease marked by pronounced sexual dimorphism. PAH disproportionately affects females, while males exhibit worse right ventricular function and survival, implicating complex biological mechanisms driven by sex chromosomes, hormones, and genetic and epigenetic regulation. Persistent gaps in sex-based reporting and analysis continue to impede mechanistic insight, reproducibility, and translational progress. This Perspective calls for a systematic shift in pulmonary vascular research toward rigorous integration of sex as a biological variable (SABV). We synthesize emerging evidence demonstrating sex-dependent differences in pulmonary vascular remodeling, right ventricular adaptation, extracellular matrix composition, and cellular responses to mechanical and hormonal cues. We highlight how unreported sex of cells, animals, and biological reagents such as hormone-containing sera introduces hidden bias and limits reproducibility. Advances in biomaterials, genetically informed animal models, and hormone-aware experimental systems now offer new opportunities to interrogate SABV mechanistically. Finally, we propose a practical framework to improve transparency, including standardized sex-based metadata, sex disaggregated data sharing, and SABV aware analytical and computational approaches. Recognizing sex as a fundamental biological variable will enhance rigor and accelerate discovery, supporting the development of more precise and effective therapies for pulmonary vascular disease.
Publisher DOI
The role of endothelial HIF-1α in vascular and alveolar development in a neonatal murine model of Bronchopulmonary Dysplasia
Figshare · 2026-05-08
otherOpen access1st authorCorresponding
Supplemental Data Supplemental Figure 1: Endothelial cell type composition and Hif-2α expression in Hif-1α ECKO and control lungs under room air and hyperoxic conditions. (A) Stacked bar plots showing the proportional distribution of endothelial cell subtypes: arterial, venous, aerocyte capillary (aCap), general capillary (gCap), proliferating gCap (Prolif gCap), and lymphatic endothelial cells within each biological replicate, based on deconvolution analysis of the bulk RNA-seq data from sorted lung endothelial cells. (B) Box plots depicting normalized expression counts of Hif-2α in Hif-1α fl/fl (blue) and Hif-1α ECKO (red) pulmonary endothelial cells under Room Air and Oxygen conditions.Supplemental Figure 2: A) Component genes under the vascular permeability pathway are positively enriched in hyperoxia-exposed lung endothelial cells (both Hif-1α fl/fl and Hif-1α ECKO ) shown as box plots and heat map. B) Component genes under the TGF-beta pathway are positively enriched in hyperoxia-exposed lung endothelial cells from Hif-1α ECKO mice, shown as box plots and heat map.Supplemental Figure 3: Hif-1α expression in murine models of and in human BPD at single-cell resolution. Dot plots depicting scaled average expression (color scale) and percentage of cells expressing Hif1a (mouse) or HIF1A (human) (dot size) across major lung cell types (top panels) and endothelial cell subtypes (bottom panels). (A) Single-cell RNA-sequencing data from Hurskainen et al. (2021) in mouse postnatal day 14 (P14) lungs exposed to hyperoxia (Oxygen, 85%, PND1-14) or room air (Normoxia). (B) Single-cell RNA-sequencing data from Cantú et al. (2022) in mouse postnatal day 7 (PND7) lungs exposed to hyperoxia (Oxygen, 95%, PND1-5) or room air (Normoxia). Endothelial subtypes include general capillary (gCap), aerocyte capillary (aCap), proliferating gCap (Prolif gCap), reactive aCap (Reactive aCap), arterial, venous, and lymphatic endothelial cells. (C) LungMAP human single-cell RNA-sequencing data across four disease states: Control, Active Evolving BPD, Chronic BPD, and Healed BPD. Endothelial cell subtypes include aerocyte capillary endothelial cells (AEC), general capillary endothelial cells (CAP1, CAP2), lymphatic endothelial cells (LEC), and vascular endothelial cells (VEC). 
Publisher DOI
Echocardiographic Detection of Pulmonary Hypertension and Right Ventricular Failure in Infants with Bronchopulmonary Dysplasia: A Survey of the BPD Collaborative
Children · 2026-05-05
articleOpen access
Background: Echocardiography is a non-invasive test that is readily used to detect pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH) and right ventricular failure (RVF). However, the most feasible, reproducible and accurate parameters to measure and use for guidance in addressing patient care have not been established and may differ between subspecialties. Methods: We surveyed members of the BPD Collaborative to determine how different care providers clinically evaluate infants for BPD-PH and RVF. Perceived challenges and obstacles that limit the utility of echocardiography are also reported. Results: Of the 108 survey respondents from ~45 centers, 55.6% were neonatologists, 18.5% were pediatric pulmonologists or pediatric intensive care physicians, 15.7% were pediatric cardiologists or pulmonary hypertension specialists, and 10.2% were other providers. Responses revealed discrepancies between specialists concerning the use of standard echocardiographic protocols and parameters that can be measured serially with relative ease, metrics that should be used to best define and distinguish the severity of BPD-PH or RVF, and parameter values that should be used to determine whether changes in PH-targeted medical therapies, hemodynamic or respiratory support are needed. Free text responses identified patient-, protocol-, cardiology-, technician-, and BPD-PH definition-related obstacles that may limit the reliable utility of echocardiography. Conclusions: Although most providers agree that echocardiography is feasible and of value, variability exists between subspecialists and centers, suggesting the need for improved standardization of imaging protocols and BPD-PH definition, consistent test interpretation, and effective communication of results to improve the reproducibility and accuracy of echocardiography in infants with BPD.
Publisher DOI
Examining the role of biologic sex on kidney outcomes in preterm neonates: A secondary analysis of the PENUT/REPAIReD study
Pediatric Nephrology · 2026-03-12
articleOpen access
BACKGROUND: Biological sex plays a crucial role in the pathophysiology of morbidities related to preterm birth. Studies specifically investigating the role of biological sex in neonatal kidney disease are lacking. This study aimed to determine the association between biological sex and kidney outcomes in preterm infants. We hypothesized that male infants would be more likely to have poor kidney outcomes, including acute kidney injury (AKI), hypertension and chronic kidney disease. Given data on the relationship between sex, AKI and lung disease, we also evaluated lung disease as a secondary outcome. METHODS: Retrospective analysis of the Preterm Erythropoietin Neuroprotection Trial data. For adjusted models, we used covariates associated with adverse outcomes a priori (gestational age, SGA status) and a lasso regression. AKI was defined using creatinine only neonatal modified KDIGO criteria and bronchopulmonary dysplasia (BPD) by Neonatal Research Network criteria. RESULTS: Of the 923 infants included, 479 (51.8%) were male. AKI was more common among males (aOR 1.31, 95%CI 1.00-1.74). Hypertension was nearly twice as common in males (66.4% vs. 51.5%, p < 0.001) and remained after adjustment (aOR 1.91, 95%CI 1.32-2.77). Severe BPD was more common in males (33.4% vs. 24.3%, p = 0.0024), which persisted after adjustment (aOR 1.65, 95%CI 1.22-2.23). This association was not fully mitigated by AKI exposure. CONCLUSIONS: We describe differences in kidney outcomes and BPD by sex. Male sex is associated with an increased risk of AKI and hypertension. Research efforts focused on the mechanisms underlying sex-specific differences are needed for the identification of novel therapies that benefit both sexes.
Publisher OA PDF DOI
The role of endothelial HIF-1α in vascular and alveolar development in a neonatal murine model of Bronchopulmonary Dysplasia
Figshare · 2026-05-08
otherOpen access1st authorCorresponding
Supplemental Data Supplemental Figure 1: Endothelial cell type composition and Hif-2α expression in Hif-1α ECKO and control lungs under room air and hyperoxic conditions. (A) Stacked bar plots showing the proportional distribution of endothelial cell subtypes: arterial, venous, aerocyte capillary (aCap), general capillary (gCap), proliferating gCap (Prolif gCap), and lymphatic endothelial cells within each biological replicate, based on deconvolution analysis of the bulk RNA-seq data from sorted lung endothelial cells. (B) Box plots depicting normalized expression counts of Hif-2α in Hif-1α fl/fl (blue) and Hif-1α ECKO (red) pulmonary endothelial cells under Room Air and Oxygen conditions.Supplemental Figure 2: A) Component genes under the vascular permeability pathway are positively enriched in hyperoxia-exposed lung endothelial cells (both Hif-1α fl/fl and Hif-1α ECKO ) shown as box plots and heat map. B) Component genes under the TGF-beta pathway are positively enriched in hyperoxia-exposed lung endothelial cells from Hif-1α ECKO mice, shown as box plots and heat map.Supplemental Figure 3: Hif-1α expression in murine models of and in human BPD at single-cell resolution. Dot plots depicting scaled average expression (color scale) and percentage of cells expressing Hif1a (mouse) or HIF1A (human) (dot size) across major lung cell types (top panels) and endothelial cell subtypes (bottom panels). (A) Single-cell RNA-sequencing data from Hurskainen et al. (2021) in mouse postnatal day 14 (P14) lungs exposed to hyperoxia (Oxygen, 85%, PND1-14) or room air (Normoxia). (B) Single-cell RNA-sequencing data from Cantú et al. (2022) in mouse postnatal day 7 (PND7) lungs exposed to hyperoxia (Oxygen, 95%, PND1-5) or room air (Normoxia). Endothelial subtypes include general capillary (gCap), aerocyte capillary (aCap), proliferating gCap (Prolif gCap), reactive aCap (Reactive aCap), arterial, venous, and lymphatic endothelial cells. (C) LungMAP human single-cell RNA-sequencing data across four disease states: Control, Active Evolving BPD, Chronic BPD, and Healed BPD. Endothelial cell subtypes include aerocyte capillary endothelial cells (AEC), general capillary endothelial cells (CAP1, CAP2), lymphatic endothelial cells (LEC), and vascular endothelial cells (VEC). 
Publisher DOI
Patient-derived lung organoids from bronchoalveolar lavage capture epithelial heterogeneity and disease biology in bronchopulmonary dysplasia
Redox Biology · 2026-01-27
articleOpen accessSenior author
Modeling neonatal lung disease ex vivo to elucidate disease pathogenesis is particularly challenging. We hypothesized that airway organoids derived from bronchoalveolar lavage (BAL) samples obtained from intubated preterm infants with bronchopulmonary dysplasia (BPD) will recapitulate the epithelial heterogeneity seen in human airways and can be used to study lung injury and therapeutic responses. Here, we demonstrate that BAL sample-derived airway organoids from ventilator-dependent patients with established BPD exhibited cellular heterogeneity consistent with that observed in the human airway. Developed organoids contain basal cell progenitors and a spectrum of differentiated epithelial subtypes, including secretory, ciliated, PNECs, and hillock cells. Hyperoxia exposure and treatment with dexamethasone caused significant cellular transcriptional changes and highlighted biological pathways, both known and novel, with distinct findings based on sex as a biological variable. Findings were validated in an independent dataset from human BPD lung samples. Infant BAL-derived human lung organoids represent a cutting-edge model that bridges a critical gap in BPD research. They combine the advantages of being patient-specific and capturing developmental lung biology, with the experimental flexibility of an in vitro system.
Publisher DOI
CD44 is critical for TLR4-mediated NLRP3 inflammasome activation and the development of BPD
American Journal of Respiratory Cell and Molecular Biology · 2026-02-10
article
RATIONALE: Bronchopulmonary Dysplasia is a chronic lung disease of preterm infants. We previously established the NLRP3 inflammasome as critical in the pathogenesis of BPD. The hyaluronan receptor CD44 interacts with TLR4 to propagate extracellular signals driving inflammation. The role of CD44 in BPD is unclear. OBJECTIVES: To determine the contribution of CD44 to NLRP3 inflammasome activation and the development of BPD. METHODS: The activation of the NLRP3 inflammasome and the development of BPD was studied in CD44 and TLR4 knockout mice. LPS was used to study TLR4-specific responses. MAIN RESULTS: In normal mice, lung CD44 decreased in the first two postnatal weeks but increased with exposure to neonatal hyperoxia. CD44 KO mice exposed to hyperoxia were protected from decreased alveolarization and inflammatory responses. Increased IL1ß mRNA and protein and cleaved caspase-1 observed in CD44 WT mice were not seen in CD44 KO mice, indicating a failure to activate the NLRP3 inflammasome. Intraperitoneal LPS resulted in increased plasma IL1ß concentrations in CD44 WT mice, which was decreased in CD44 KO mice. Intratracheal LPS caused a neutrophilic inflammation in CD44 WT lungs, which was absent in CD44 KO mice. TLR4 KO mice were protected from neonatal hyperoxia and showed less lung IL1ß and inflammation. Increased lung CD44 expression was observed in the lungs of preterm baboons developing experimental BPD and in lungs of preterm born humans at extended corrected ages. CONCLUSIONS: Collectively, these data implicate CD44 in the pathogenesis of BPD and identify a novel therapeutic target to limit NLRP3 inflammasome activation.
Publisher DOI
Spatial Transcriptomics Resolve Surfactant and Ciliary Deficits in Bronchopulmonary Dysplasia
American Journal of Respiratory and Critical Care Medicine · 2025-05-01
article
Abstract Background: Bronchopulmonary Dysplasia (BPD) is a chronic lung disease of premature infants, representing a major cause of morbidity, mortality, and increased healthcare costs. It is strongly linked to poorer neurodevelopmental outcomes and heightened vulnerability to lower respiratory tract infections (LRTI), which drive frequent hospital readmissions in early childhood. Despite these well-documented challenges, the mechanisms underlying BPD patients’ increased susceptibility to LRTI remain unclear. Objective: This study aimed to investigate the molecular changes in BPD lungs that may contribute to LRTI susceptibility using advanced spatial transcriptomics. Methods: Using the GeoMX Digital Spatial Profiler, we conducted whole transcriptome analysis on formalin-fixed paraffin-embedded (FFPE) lung tissue from 9 BPD patients and 9 age-matched controls who died of non-respiratory causes. We analyzed gene expression across airway, vessel, and parenchymal regions of interest (ROIs). High-confidence transcriptional target intersection analysis identified key networks altered in BPD. Findings were validated by immunofluorescence staining in consecutive FFPE sections. Results: Out of 18,000 genes analyzed, 8,765 were expressed above background. BPD lungs exhibited a marked reduction in surfactant proteins A and D in the parenchyma, alongside decreased expression of cilia-related genes in the airways. Cell deconvolution analysis revealed reduced alveolar type 2 (AT2) cells in the parenchyma and decreased ciliated and deuterostomal (ciliated precursor) cells in the airway epithelium. These findings highlight significant impairments in two critical components of pulmonary innate immunity: surfactant proteins, essential for pathogen clearance in the parenchyma, and ciliated epithelial cells, vital for mucociliary clearance. Notably, we identified a strong positive correlation between reduced surfactant protein levels and diminished cilia function, providing insight into the interplay between these systems in BPD pathology.Conclusion: This study provides novel evidence that reductions in surfactant proteins and ciliated epithelial cells contribute to the compromised immune defenses of BPD lungs. These findings offer a mechanistic basis for the heightened susceptibility to LRTI in BPD patients, emphasizing the need for targeted therapeutic strategies to address these deficiencies and reduce the burden of respiratory infections in this vulnerable population.
Publisher DOI
Unlocking the Therapeutic Code of Mesenchymal Stromal Cells
American Journal of Respiratory and Critical Care Medicine · 2025-01-23
letterOpen access1st authorCorresponding
Publisher OA PDF DOI
Tissue-resident Alveolar Macrophages as Drivers of Sex-specific Differences Across the Lifespan
American Journal of Respiratory and Critical Care Medicine · 2025-05-01
articleSenior author
Abstract Background: Investigating mechanisms underlying sex differences in lung diseases holds significant implications for human health. Sex as a biological variable modulates disease pathophysiology across the lifespan including Bronchopulmonary dysplasia (BPD) and COPD. The lung macrophages play a crucial role in health and disease. Sexual dimorphism significantly impacts the phenotype and function of tissue-resident macrophages. Objective: We tested the hypothesis that biological sex plays a crucial role in the transcriptional state, redox state, and mitochondrial function of alveolar macrophages (AMs) using a neonatal murine hyperoxia-induced lung injury as a relevant model for human BPD. Methods: We used scRNA-seq data from postnatal day (PND) 1 murine lung and pre-existing single-cell datasets of the embryonic mouse lung and adult human bronchoalveolar lavage (BAL) samples. Bulk-RNA seq was performed on sorted alveolar macrophages from PND7 male and female neonatal lung after hyperoxia exposure (95% FiO2; PND1-5). Optical redox imaging to measure the intrinsic fluorescence of oxidized flavoproteins (Fp containing flavin adenine dinucleotide (FAD)) and reduced nicotinamide adenine dinucleotide (NADH) were done on male and female AMs at baseline and after exposure to hyperoxia. Intact cell bioenergetics were measured using an XF analyzer (Agilent Technologies) and various mitochondrial effectors. Results: First, we used the Augur bioinformatic pipeline to prioritize the cell types in the most responsive to biological sex. We identified that alveolar macrophages (in the PND1 mouse lung), and prenatal perivascular macrophages (in the embryonic lung) were the most distinct based on biological sex in the developing murine lung (Fig. 1A-B). Similarly, alveolar macrophages were the most distinct in adult BAL samples (Fig. 2A-B). Bulk RNA-Seq analysis of sorted alveolar macrophages (PND7 room-air and hyperoxia-exposed) revealed distinct biological pathways enriched in male and female AMs (Fig 3A). Significantly, in males, enrichment of glycolytic pathways was seen, and females showed enrichment for pathways related to aerobic electron transport chain and oxidative phosphorylation. Significant differences were seen in human male and female control and COPD AMs. Finally, we used optical metabolic imaging to assess the redox status of the male and female AMs (Fig. 3B-C). After 48 h hyperoxia exposure, Fp and the redox ratio were significantly increased in male but not female AMs. Marked differences were noted in male and female AM cellular bioenergetics. Basal and maximal oxygen consumption rate were higher in female AMs. Conclusions: Sex-specific differences in alveolar macrophage response to injury may underlie the differences in disease pathophysiology and response to therapy.
Publisher DOI

Recent grants

Sex as biological variable in Bronchopulmonary Dysplasia: Role of the Notch pathway
NIH · $441k · 2020–2023
Mechanisms of sex specific differences in neonatal hyperoxic lung injury
NIH · $816k · 2015–2020
Sex-specific differences in neonatal hyperoxic lung injury: Role of the NF-kappa B pathway
NIH · $159k · 2018–2020
Leveraging multiomics and advanced mouse models to delineate mechanisms underlying sex‐specific differences in recovery and repair after neonatal hyperoxia exposure in the developing lung
NIH · $1.6M · 2020–2025
Mechanisms of sex differences in neonatal pulmonary oxygen toxicity
NIH · $2.7M · 2019–2026

Frequent coauthors

Bhagavatula Moorthy
Baylor College of Medicine
98 shared
Weiwu Jiang
Baylor College of Medicine
70 shared
Xanthi I. Couroucli
Baylor College of Medicine
60 shared
Manuel Cantu Gutierrez
Children's Hospital of Philadelphia
51 shared
Abiud Cantu
Children's Hospital of Philadelphia
39 shared
Connor C. Leek
Children's Hospital of Philadelphia
27 shared
Cristian Coarfa
24 shared
Lihua Wang
First Affiliated Hospital of Bengbu Medical College
21 shared

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