- Pulmonary Disease
Fellowship: Stanford University Pulmonary and Critical Care Fellowship (2018) CA
Residency: LACplusUSC Medical Center Internal Medicine Residency (2015) CA
Board Certification: American Board of Internal Medicine, Pulmonary Disease (2018)
Board Certification: American Board of Internal Medicine, Critical Care Medicine (2018)
Board Certification: American Board of Internal Medicine, Internal Medicine (2015)
Medical Education: Columbia University College of Physicians and Surgeons (2012) NY
Current Research and Scholarly Interests
Molecular and cellular biology of the distal lung
High altitude medicine
KRAS(G12D) drives lepidic adenocarcinoma through stem-cell reprogramming.
Many cancers originate from stem or progenitor cells hijacked by somatic mutations that drive replication, exemplified by adenomatous transformation of pulmonary alveolar epithelial type II (AT2) cells1. Here we demonstrate a different scenario: expression of KRAS(G12D) in differentiated AT1 cells reprograms them slowly and asynchronously back into AT2 stem cells that go on to generate indolent tumours. Like human lepidic adenocarcinoma, the tumour cells slowly spread along alveolar walls in a non-destructive manner and have low ERK activity. We find that AT1 and AT2 cells act as distinct cells of origin and manifest divergent responses to concomitant WNT activation and KRAS(G12D) induction, which accelerates AT2-derived but inhibits AT1-derived adenoma proliferation. Augmentation of ERK activity in KRAS(G12D)-induced AT1 cells increases transformation efficiency, proliferation and progression from lepidic to mixed tumour histology. Overall, we have identified a new cell of origin for lung adenocarcinoma, the AT1 cell, which recapitulates features of human lepidic cancer. In so doing, we also uncover a capacity for oncogenic KRAS to reprogram a differentiated and quiescent cell back into its parent stem cell en route to adenomatous transformation. Our work further reveals that irrespective of a given cancer's current molecular profile and driver oncogene, the cell of origin exerts a pervasive and perduring influence on its subsequent behaviour.
View details for DOI 10.1038/s41586-023-06324-w
View details for PubMedID 37468622
View details for PubMedCentralID 4013278
WNT7A deficit is associated with dysfunctional angiogenesis in pulmonary arterial hypertension.
The European respiratory journal
INTRODUCTION: Pulmonary arterial hypertension (PAH) is characterized by loss of microvessels. The Wnt pathways control pulmonary angiogenesis, but their role in PAH is incompletely understood. We hypothesized that Wnt activation in pulmonary microvascular endothelial cells (PMVECs) is required for pulmonary angiogenesis, and its loss contributes to PAH.METHODS: Lung tissue and PMVECs from healthy and PAH patients were screened for Wnt production. Global and endothelial-specific Wnt7a-/- mice were generated and exposed to chronic hypoxia and Sugen-hypoxia (SuHx).RESULTS: Healthy PMVECs demonstrated >6-fold Wnt7a expression during angiogenesis that was absent in PAH PMVECs and lungs. Wnt7a expression correlated with formation of tip cells, a migratory endothelial phenotype critical for angiogenesis. PAH PMVECs demonstrated reduced VEGF-induced tip cell formation as evidenced by reduced filopodia formation and motility, which was partially rescued by recombinant Wnt7a. We discovered that Wnt7a promotes VEGF signaling by facilitating Y1175 tyrosine phosphorylation in VEGFR2 through ROR2, a Wnt-specific receptor. We found that ROR2 knockdown mimics Wnt7a insufficiency and prevents recovery of tip cell formation with Wnt7a stimulation. While there was no difference between wild-type and endothelial-specific Wnt7a-/- mice under either chronic hypoxia and SuHx, global Wnt7a+/- mice in hypoxia demonstrated higher pulmonary pressures and severe right ventricular and lung vascular remodeling. Similar to PAH, Wnt7a+/- PMVECs exhibited insufficient angiogenic response to VEGF-A that improved with Wnt7a.CONCLUSIONS: Wnt7a promotes VEGF signaling in lung PMVECs and its loss is associated with insufficient VEGF-A angiogenic response. We propose that Wnt7a deficiency contributes to progressive small vessel loss in PAH.
View details for DOI 10.1183/13993003.01625-2022
View details for PubMedID 37024132
Predictive Capacity of Pulmonary Function Tests for Acute Mountain Sickness.
High altitude medicine & biology
Small, Elan, Nicholas Juul, David Pomeranz, Patrick Burns, Caleb Phillips, Mary Cheffers, and Grant S. Lipman. Predictive capacity of pulmonary function tests for acute mountain sickness. High Alt Med Biol. 00:000-000, 2021. Background: Pulmonary function as measured by spirometry has been investigated at altitude with heterogenous results, though data focused on spirometry and acute mountain sickness (AMS) are limited. The objective of this study was to investigate the capacity of pulmonary function tests (PFTs) to predict the development of AMS. Materials and Methods: This study was a blinded prospective observational study run during a randomized controlled trial comparing acetazolamide, budesonide, and placebo for AMS prevention on White Mountain, CA. Spirometry measurements of forced expiratory volume in one second (FEV1), forced vital capacity (FVC), and peak expiratory flow were taken at a baseline altitude of 1,250 m, and the evening of and morning after ascent to 3,810 m. Measurements were assessed for correlation with AMS. Results: One hundred three participants were analyzed with well-matched baseline demographics and AMS incidence of 75 (73%) and severe AMS of 48 (47%). There were no statistically significant associations between changes in mean spirometry values on ascent to high altitude with incidence of AMS or severe AMS. Lake Louise Questionnaire scores were negatively correlated with FVC (r = -0.31) and FEV1 (r = -0.29) the night of ascent. Baseline PFT had a predictive accuracy of 65%-73% for AMS, with a receiver operating characteristic of 0.51-0.65. Conclusions: Spirometry did not demonstrate statistically significant changes on ascent to high altitude, nor were there significant associations with incidence of AMS or severe AMS. Low-altitude spirometry did not accurately predict development of AMS, and it should not be recommended for risk stratification.
View details for DOI 10.1089/ham.2020.0150
View details for PubMedID 33601996
Niche Cells and Signals that Regulate Lung Alveolar Stem Cells In Vivo.
Cold Spring Harbor perspectives in biology
The distal lung is a honeycomb-like collection of delicate gas exchange sacs called alveoli lined by two interspersed epithelial cell types: the cuboidal, surfactant-producing alveolar type II (AT2) and the flat, gas-exchanging alveolar type I (AT1) cell. During aging, a subset of AT2 cells expressing the canonical Wnt target gene, Axin2, function as stem cells, renewing themselves while generating new AT1 and AT2 cells. Wnt activity endows AT2 cells with proliferative competency, enabling them to respond to activating cues, and simultaneously blocks AT2 to AT1 cell transdifferentiation. Acute alveolar injury rapidly expands the AT2 stem cell pool by transiently inducing Wnt signaling activity in "bulk" AT2 cells, facilitating rapid epithelial repair. AT2 cell "stemness" is thus tightly regulated by access to Wnts, supplied by a specialized single-cell fibroblast niche during maintenance and by AT2 cells themselves during injury repair. Two non-AT2 "reserve" cell populations residing in the distal airways also contribute to alveolar repair, but only after widespread epithelial injury, when they rapidly proliferate, migrate, and differentiate into airway and alveolar lineages. Here, we review alveolar renewal and repair with a focus on the niches, rather than the stem cells, highlighting what is known about the cellular and molecular mechanisms by which they control stem cell activity in vivo.
View details for DOI 10.1101/cshperspect.a035717
View details for PubMedID 32179507
- Interstitial Pulmonary Edema Assessed by Lung Ultrasound on Ascent to High Altitude and Slight Association with Acute Mountain Sickness: A Prospective Observational Study HIGH ALTITUDE MEDICINE & BIOLOGY 2019
Interstitial Pulmonary Edema Assessed by Lung Ultrasound on Ascent to High Altitude and Slight Association with Acute Mountain Sickness: A Prospective Observational Study.
High altitude medicine & biology
Alsup, Carl, Grant S. Lipman, David Pomeranz, Rwo-Wen Huang, Patrick Burns, Nicholas Juul, Caleb Phillips, Carrie Jurkiewicz, Mary Cheffers, Christina Evans, Anirudh Saraswathula, Peter Baumeister, Lucinda Lai, Jessica Rainey, and Viveta Lobo. Interstitial pulmonary edema assessed by lung ultrasound on ascent to high altitude and slight association with acute mountain sickness: A prospective observational study. High Alt Med Biol. 00:000-000, 2019. Background: Acute mountain sickness (AMS) is a common disease that may have a pulmonary component, as suggested by interstitial pulmonary edema quantified by the B-line score (BLS) on ultrasound (US). This subclinical pulmonary edema has been shown to increase with ascent to high altitude and AMS severity, but has not been prospectively associated with AMS incidence in a large prospective study. Materials and Methods: This prospective observational study was part of a randomized controlled trial enrolling healthy adults over four weekends ascending White Mountain, California. Subjects were assessed by lung US and the Lake Louise Questionnaire at 4110 ft (1240 m), upon ascent to 12,500 ft (3810 m), and the next morning at 12,500 ft (3810 m). Results: Three hundred five USs in total were completed on 103 participants, with 73% total incidence of AMS. The mean (±standard deviation) BLS increased from baseline (1.15 ± 1.80) to high altitude (2.56 ± 2.86), a difference of 1.37 (±2.48) (p = 0.04). Overall BLS was found, on average, to be higher among those diagnosed with AMS than without (2.97 vs. 2.0, p = 0.04, 95% confidence interval [CI] -∞ to -0.04). The change in BLS (ΔBLS) from low altitude baseline was significantly associated with AMS (0.88 vs. 1.72, r2 = 0.023, 95% CI -∞ to -0.01, p = 0.048). Conclusions: Interstitial subclinical pulmonary edema by lung US was found to have a small but significant association with AMS.
View details for PubMedID 31045443
Combinations of differentiation markers distinguish subpopulations of alveolar epithelial cells in adult lung.
American journal of physiology. Lung cellular and molecular physiology
2016; 310 (2): L114-20
Distal lung epithelium is maintained by proliferation of alveolar type II (AT2) cells and, for some daughter AT2 cells, transdifferentiation into alveolar type I (AT1) cells. We investigated if subpopulations of alveolar epithelial cells (AEC) exist that represent various stages in transdifferentiation from AT2 to AT1 cell phenotypes in normal adult lung and if they can be identified using combinations of cell-specific markers. Immunofluorescence microscopy showed that, in distal rat and mouse lungs, ∼ 20-30% of NKX2.1(+) (or thyroid transcription factor 1(+)) cells did not colocalize with pro-surfactant protein C (pro-SP-C), a highly specific AT2 cell marker. In distal rat lung, NKX2.1(+) cells coexpressed either pro-SP-C or the AT1 cell marker homeodomain only protein x (HOPX). Not all HOPX(+) cells colocalize with the AT1 cell marker aquaporin 5 (AQP5), and some AQP5(+) cells were NKX2.1(+). HOPX was expressed earlier than AQP5 during transdifferentiation in rat AEC primary culture, with robust expression of both by day 7. We speculate that NKX2.1 and pro-SP-C colocalize in AT2 cells, NKX2.1 and HOPX or AQP5 colocalize in intermediate or transitional cells, and HOPX and AQP5 are expressed without NKX2.1 in AT1 cells. These findings suggest marked heterogeneity among cells previously identified as exclusively AT1 or AT2 cells, implying the presence of subpopulations of intermediate or transitional AEC in normal adult lung.
View details for DOI 10.1152/ajplung.00337.2015
View details for PubMedID 26545903
View details for PubMedCentralID PMC4719049