Biology subjects

Mukhitov, A. R.

Publications and source records attributed to Mukhitov, A. R..

2 recordsLinked to original sources

bioRxiv2022

Hyperactive mTOR in Lung Mesenchyme Induces Endothelial Dysfunction and Pulmonary Vascular Remodeling

Pulmonary vascular remodeling is the key structural abnormality in pulmonary hypertension (PH). Mechanistic target of rapamycin (mTOR) has long been suspected to play a role in the development of pulmonary vascular remodeling. However, underlying cellular and molecular mechanisms leading to this pathophysiological condition remain incompletely understood. To elucidate the crosstalk between lung mesenchyme with activated mTOR and endothelial cells (ECs), we focused on a monogenic lung disease, pulmonary lymphangioleiomyomatosis (LAM). LAM is a progressive cystic lung disease caused by a mutational inactivation of tuberous sclerosis complex (TSC1/TSC2), which results in constitutive mTOR activation in mesenchymal LAM cells. ECs derived from LAM lung explants showed increased proliferation, migration, and defective angiogenesis compared to age- and sex-matched ECs from control human lung. In LAM cells, we found increased WNT2 ligand expression. We also identified corresponding Frizzled 4 (FZD) receptors on ECs isolated from distal LAM lung, suggesting cellular crosstalk between LAM cells and ECs. In endothelial-fibroblast cocultures, treatment of normal ECs with WNT2 ligands recapitulated LAM EC phenotype and morphology. We observed transcriptomic upregulation in metabolic, angiogenic and growth pathways in ECs of young mice, while 1-year-old Tsc2KO mice spontaneously developed pulmonary vascular remodeling with concurrent elevation in right ventricular systolic pressure. Our study demonstrates that LAM cells are not just a pathological mesenchymal cell state but a signaling hub that contributes to dysregulated cellular response in the surrounding vasculature, eventual pulmonary vascular remodeling and PH.

molecular biology↗

bioRxiv2022

Nanoparticle-induced augmentation of neutrophils' phagocytosis of bacteria

Despite the power of antibiotics, bacterial infections remain a major killer, due to antibiotic resistance and hosts with dysregulated immune systems. We and others have been developing drug-loaded nanoparticles that home to the sites of infection and inflammation via engineered tropism for neutrophils, the first-responder leukocytes in bacterial infections. Here, we examined how a member of a broad class of neutrophil-tropic nanoparticles affects neutrophil behavior, specifically questioning whether the nanoparticles attenuate an important function, bacterial phagocytosis. We found these nanoparticles actually augment phagocytosis of non-opsonized bacteria, increasing it by ~50%. We showed this augmentation of phagocytosis is likely co-opting an evolved response, as opsonized bacteria also augment phagocytosis of non-opsonized bacteria. Enhancing phagocytosis of non-opsonized bacteria may prove particularly beneficial in two clinical situations: in hypocomplementemic patients (meaning low levels of the main bacterial opsonins, complement proteins, seen in conditions such as neonatal sepsis and liver failure) or for bacteria that are largely resistant to complement opsonization (e.g., Neisseria). Additionally, we observe that; a) prior treatment with bacteria augments neutrophil uptake of neutrophil-tropic nanoparticles; b) neutrophil-tropic nanoparticles colocalize with bacteria inside of neutrophils. The observation that neutrophil-tropic nanoparticles enhance neutrophil phagocytosis and localize with bacteria inside neutrophils suggests that these nanoparticles will serve as useful carriers for drugs to ameliorate bacterial diseases.

immunology↗