Biology subjects

Hariri, L. P.

Publications and source records attributed to Hariri, L. P..

3 recordsLinked to original sources

bioRxiv2023

Simultaneous PET and molecular MR imaging of cardiopulmonary fibrosis in a mouse model of left ventricular dysfunction

BackgroundAging-associated left ventricular (LV) dysfunction promotes cardiopulmonary fibrogenic remodeling, Group 2 pulmonary hypertension (PH), and right ventricular failure. At the time of diagnosis, cardiac function has declined, and cardiopulmonary fibrosis has often developed. Here, we sought to develop a molecular positron emission tomography (PET)-magnetic resonance imaging (MRI) protocol to detect both cardiopulmonary fibrosis and fibrotic disease activity in an LV dysfunction model. MethodsLV dysfunction was induced by transverse aortic constriction (TAC) in 6-month-old senescence-accelerated prone (SAMP8) mice, a subset of mice received sham surgery. Three weeks post-surgery, mice underwent simultaneous PET-MR imaging at 4.7 T. Collagen-targeted PET and fibrogenesis MR probes were intravenously administered. PET signal was computed as myocardium- or lung-to-muscle ratio (MMR, LMR). Percent signal increase (%SI) and {Delta}LMR were computed from the pre-/post-injection MR images. Tissue specimens were analyzed for hydroxyproline (Hyp) and allysine content. Ventricular structure and function were measured by echocardiography and hemodynamic pressure-volume (PV) loop analysis. ResultsAllysine in the heart (22{+/-}5 (TAC), 13{+/-}5 (sham) nmol/g, P=0.02) and lungs (7.5{+/-}4 (TAC), 5.8{+/-}2 (sham) nmol/lung, P=0.17) of TAC mice corresponded to an increase in myocardial MRI %SI (29{+/-}15 (TAC), 6.1{+/-}4 (sham), P<0.0001) and {Delta}LMR (0.3{+/-}0.1 (TAC), 0.08{+/-}0.1 (sham), P<0.0001). Hyp in the heart (555{+/-}90 (TAC), 400{+/-}80 (sham) {micro}g/g, P<0.0001) and lungs (189{+/-}63 (TAC), 143{+/-}31 (sham) {micro}g/lung, P<0.01) were elevated in TAC mice, which corresponded to an increase in PET signal (MMR: 1.8{+/-}0.1 (TAC), 1.6{+/-}0.2 (sham), P=0.02; LMR: 1.5{+/-}0.1 (TAC), 1.2{+/-}0.1 (sham), P<0.001). PV loop and echocardiography demonstrated adverse LV remodeling, function, and increased right ventricular systolic pressure in TAC mice. ConclusionsAdministration of collagen-targeted PET and allysine-targeted MR probes led to elevated PET-MRI signals in the myocardium and lungs of TAC mice. The study demonstrates the potential to detect fibrosis and fibrogenesis in cardiopulmonary disease through a dual molecular PET-MR imaging protocol.

molecular biology↗

bioRxiv2023

Tailored chemical reactivity probes for systemic imaging of aldehydes in fibroproliferative diseases

During fibroproliferation, protein-associated extracellular aldehydes are formed by the oxidation of lysine residues on extracellular matrix proteins to form the aldehyde allysine. Here we report three Mn(II)-based, small molecule magnetic resonance (MR) probes that contain -effect nucleophiles to target allysine in vivo and report on tissue fibrogenesis. We used a rational design approach to develop turn-on probes with a 4-fold increase in relaxivity upon targeting. The effects of aldehyde condensation rate and hydrolysis kinetics on the performance of the probes to detect tissue fibrogenesis noninvasively in mouse models were evaluated by a systemic aldehyde tracking approach. We showed that for highly reversible ligations, off-rate was a stronger predictor of in vivo efficiency, enabling histologically validated, three-dimensional characterization of pulmonary fibrogenesis throughout the entire lung. The exclusive renal elimination of these probes allowed for rapid imaging of liver fibrosis. Reducing the hydrolysis rate by forming an oxime bond with allysine enabled delayed phase imaging of kidney fibrogenesis. The imaging efficacy of these probes, coupled with their rapid and complete elimination from the body, make them strong candidates for clinical translation.

biochemistry↗

bioRxiv2020

Pretreatment of aged mice with retinoic acid restores alveolar regeneration via upregulation of reciprocal PDGFRA signaling

ObjectivesIdiopathic Pulmonary Fibrosis (IPF) primarily affects the aged population and is characterized by failure of alveolar regeneration leading to loss of alveolar type 1 cells (AT1). Aged mouse models of lung repair have demonstrated that regeneration fails with increased age. Mouse and rat lung repair models have shown retinoic acid (RA) treatment can restore alveolar regeneration. Herein we seek to determine the signaling mechanisms by which RA treatment prior to injury supports alveolar differentiation. DesignPartial pneumonectomy (PNX) lung injury model and next generation sequencing of sorted cell populations are used to uncover molecular targets regulating alveolar repair. In-vitro organoids generated from Mouse or IPF patient epithelial cells co-cultured with young, aged, or RA pretreated murine mesenchyme are used to test potential targets. Main outcome measurementsKnown alveolar epithelial cell differentiation markers, including HOPX and AGER for AT1 cells are used to assess outcome of treatments. ResultsGene expression analysis of sorted fibroblasts and epithelial cells isolated from lungs of young, aged, and RA treated aged mice predicted increased PDGFA signaling that coincided with regeneration and alveolar epithelial differentiation. Addition of PDGFA induced AT1 and AT2 alveolar differentiation in both mouse and human IPF lung organoids generated with aged fibroblasts and PDGFA monoclonal antibody blocked AT1 cell differentiation in organoids generated with young murine fibroblasts. ConclusionsOur data support the concept that reciprocal PDGFA signaling activates regenerative fibroblasts that support alveolar epithelial cell differentiation and repair, providing a potential therapeutic strategy to influence the pathogenesis of IPF. Key QuestionWhich epithelial-mesenchymal crosstalk pathways are activated by RA pretreatment of aged lungs that support realveolarization after partial pneumonectomy surgery? Bottom LineIncreased PDGFA/PDGFRA signaling in aged lungs promotes regenerative activation of interstitial matrixfibroblast which is required for AT2 to AT1 differentiation and alveolar regeneration. Read OnIn-vitro and in-vivo analysis demonstrated that PDGFA signaling supports alveolar matrixfibroblast and AT1 epithelial cell differentiation, both necessary for alveolar regeneration in aged lungs.

cell biology↗