Welcome!

In our lab, we are interested in looking into the mechanisms behind sex-specific differences in lung diseases as it pertains to Neonatology.

Lung Tissue
Krithika Lingappan

Krithika Lingappan, MD, PhD, MS

Our unique niche is to elucidate the mechanisms sex-specific differences in neonatal hyperoxic lung injury with the goal to develop individualized therapeutic options to decrease morbidity in preterm babies. Sex-specific differences exist in various forms of organ injury in adults and children. Neonatal outcomes for males are worse than females for many diseases, including bronchopulmonary dysplasia (BPD). Being a neonatologist, Dr. Lingappan's interest was in the field of neonatal lung injury and repair.

Meet the rest of the lab 👩‍🔬
Sprouting Angiogenesis

Sprouting Angiogenesis in male and female human pulmonary microvascular endothelial cells.

Our research

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. We study how lung injury and repair is different between male and female neonates and elucidate the molecular mechanisms modulating these sex-specific differences.

Currently funded projects

Projects in pipeline

Mechanisms of sex differences in neonatal pulmonary oxygen toxicity.

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how small RNAs lead to sex-specific differences in lung injury in repair. This will lead to the development of novel approaches and individualized therapeutic options for BPD.

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

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how lung injury and repair is different between male and female neonates and elucidate the molecular mechanisms modulating these sex-specific differences.

Sex as biological variable in Bronchopulmonary Dysplasia: Role of the Notch pathway.

Bronchopulmonary dysplasia (BPD), a debilitating lung disease with long-term consequences, is the most common morbidity in extremely premature neonates. Male babies have a higher incidence of BPD compared to females. In this proposal, we will study how the Notch pathway could lead to sex-specific differences in lung repair after exposure to hyperoxia. This will lead to the development of novel approaches and individualized therapeutic options for BPD.

Single cell Seq experiment to look at heterogeneity in different lung cell subpopulations and sex-specific differences.

Use the Four Core Genotype mice to delineate the role of sex hormones versus sex chromosomes on lung development, injury and repair.

Lineage Tracing Models to study the cell fate of endothelial cells in lung injury and repair.

Use Endothelial cell specific AAV to deliver therapies or to temporally turn off or turn on key genes to study their role in neonatal lung injury and repair.

Latest Publications

Remarkable sex-specific differences at Single-Cell Resolution in Neonatal Hyperoxic Lung Injury.

Cantu A, Gutierrez MC, Dong X, Leek C, Sajti E, Lingappan K

American journal of physiology. Lung cellular and molecular physiology.

doi: 10.1152/ajplung.00269.2022

Published online 2022 Oct 25.

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Growth and differentiation factor 15 (GDF15) levels predict adverse respiratory outcomes in premature neonates.

Almudares F, Hagan J, Chen X, Devaraj S, Moorthy B, Lingappan K

Pediatric pulmonology.

doi: 10.1002/ppul.26197

Published online 2022 Oct 7.

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Correction to: Call to action: gender equity in neonatology.

Machut KZ, Bhombal S, Escobedo M, Kataria-Hale J, Kushnir A, Lingappan K, Oji-Mmuo CN, Owens L, Savich R, Song C, Wright R, Dammann CEL

Journal of perinatology : official journal of the California Perinatal Association.

doi: 10.1038/s41372-022-01511-5

Published online 2022 Oct 4.

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Resources

Remarkable Lung Heterogeneity at Single-Cell Resolution and the Role of Sex as a Biological Variable in Neonatal Hyperoxic Lung Injury

A. Cantu, M. Cantu, X. Dong, C. Leek, A. Wang, E. Sajti, K. Lingappan

Exposure to supraphysiological concentrations of oxygen (hyperoxia) predisposes to bronchopulmonary dysplasia (BPD), which is characterized by abnormal alveolarization and pulmonary vascular development, in preterm neonates. Neonatal hyperoxia exposure is used to recapitulate the phenotype of human BPD in murine models. Male sex is considered an independent predictor for the development of BPD, but the main mechanisms underlying sexually dimorphic outcomes are unknown. Our objective was to investigate sex-specific and cell-type specific transcriptional changes that drive injury in the neonatal lung exposed to hyperoxia at single-cell resolution and delineate the changes in cell-cell communication networks in the developing lung. We used single-cell RNA sequencing (scRNAseq) to generate transcriptional profiles of >35,000 cells isolated from the lungs of neonatal male and female C57BL/6 mice exposed to 95% between PND1-5 (saccular stage of lung development) or normoxia and euthanized at PND7 (alveolar stage of lung development). ScRNAseq identified 22 cell clusters with distinct populations of endothelial, epithelial, mesenchymal, and immune cells. Our data identified that the distal lung vascular endothelium (composed of aerocytes and general capillary endothelial cells) is exquisitely sensitive to hyperoxia exposure with the emergence of an intermediate capillary endothelial population with both general capillaries (gCap) and aerocytes or alveolar capillaries (aCap) markers. We also identified a myeloid-derived suppressor cell population from the lung neutrophils. Sex-specific differences were evident in all lung cell subpopulations but were striking among the lung immune cells. Finally, we identified that the specific intercellular communication networks and the ligand-receptor pairs that are impacted by neonatal hyperoxia exposure.

Open positions

We are looking for graduate students looking to push our research forward while learning vital skill sets for their all-round development as a scientist.

Critical Thinking

Problem Solver

Willing to learn (Growth Mindset)

Self-Motivation

Honesty

Strong work ethic

Normoxia vs Hyperoxia

Contact Us!

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Section of Neonatology, Department of Pediatrics

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lingappank AT chop DOT edu