Publications by authors named "Dmitri Pechkovsky"

Limb-girdle muscular dystrophy (MD) type 2B (LGMD2B) and Duchenne MD (DMD) are caused by mutations to the Dysferlin and Dystrophin genes, respectively. We have recently demonstrated in typically mild dysferlin- and dystrophin-deficient mouse models that increased plasma cholesterol levels severely exacerbate muscle wasting, and that DMD patients display primary dyslipidemia characterized by elevated plasma cholesterol and triglycerides. Herein, we investigate lipoprotein abnormalities in LGMD2B and if statin therapy protects dysferlin-deficient mice (Dysf) from muscle damage.

View Article and Find Full Text PDF

Background And Purpose: Losartan is an anti-hypertensive angiotensin II (ANGII) type 1 receptor (AT1R) blocker (ARB) with many unexpected therapeutic properties, even in non-blood pressure (BP)-related diseases. Administered as a prodrug, losartan undergoes serial metabolism into EXP3179, a metabolite alleged to lack AT1R-blocking properties, and EXP3174, the dominant AT1R antagonist. Having observed that losartan can decrease vascular tone in mice with low AT1R expression and inhibit Marfan aortic widening at very high doses, we investigated whether EXP3179 may have unique, AT1R-independent effects on vascular tone and endothelial function.

View Article and Find Full Text PDF
Article Synopsis
  • * IPF-LFs display heightened DNA damage response and mitochondrial dysfunction, marked by increased superoxide production and mTORC1 activation, whereas Ctrl-LFs respond differently to DNA damage and mitochondrial stress.
  • * Targeting mTORC1 and using antioxidants can reduce senescence in IPF-LFs, suggesting that better understanding the role of mitochondria in fibroblast senescence might lead to new IPF treatments.
View Article and Find Full Text PDF

Sarcoidosis is a granulomatous disease characterized by a T-helper type 1 (Th1) cell-dominated alveolitis. As a role of bacteria in the pathogenesis of sarcoidosis has been discussed, Toll-like receptors (TLRs) may be involved in the initiation of a first immune reaction. We analyzed expression and functional relevance of several TLRs in bronchoalveolar lavage (BAL) cells from patients with pulmonary sarcoidosis.

View Article and Find Full Text PDF

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease characterized by varying degrees of emphysematous lung destruction and small airway disease, each with distinct effects on clinical outcomes. There is little known about how microRNAs contribute specifically to the emphysema phenotype. We examined how genome-wide microRNA expression is altered with regional emphysema severity and how these microRNAs regulate disease-associated gene expression networks.

View Article and Find Full Text PDF

Background: Chronic obstructive pulmonary disease (COPD) is a heterogeneous disease consisting of emphysema, small airway obstruction, and/or chronic bronchitis that results in significant loss of lung function over time.

Methods: In order to gain insights into the molecular pathways underlying progression of emphysema and explore computational strategies for identifying COPD therapeutics, we profiled gene expression in lung tissue samples obtained from regions within the same lung with varying amounts of emphysematous destruction from smokers with COPD (8 regions × 8 lungs = 64 samples). Regional emphysema severity was quantified in each tissue sample using the mean linear intercept (Lm) between alveolar walls from micro-CT scans.

View Article and Find Full Text PDF

STAT3 is a latent transcription factor that plays a role in regulating fibroblast function in fibrotic lung diseases. To further understand the role of STAT3 in the phenotypic divergence and function of human lung fibroblasts (LFs), we investigated the effect of basal and cytokine-induced STAT3 activity on indices of LF differentiation and activation, including expression of α-smooth muscle actin (α-SMA), collagen, and adhesion molecules Thy-1/CD90 and α(v) β(3) and β(5) integrins. We identified a population of fibroblasts from usual interstitial pneumonia (UIP)/idiopathic pulmonary fibrosis (IPF) lungs characterized by constitutively phosphorylated STAT3, lower proliferation rates, and diminished expression of α-SMA, Thy-1/CD90, and β(3) integrins compared with control LFs.

View Article and Find Full Text PDF

Granzyme K (GrK) is a trypsin-like serine protease that is elevated in patients with sepsis and acute lung inflammation. While GrK was originally believed to function exclusively as a pro-apoptotic protease, recent studies now suggest that GrK may possess other non-cytotoxic functions. In the context of acute lung inflammation, we hypothesized that GrK induces pro-inflammatory cytokine release through the activation of protease-activated receptors.

View Article and Find Full Text PDF

For translational respiratory research including in the development of clinical diagnostic tools, a minimally invasive imaging method, which can provide both cellular and extracellular structural details with sufficient specificity, sensitivity and spatial resolution, is particularly useful. Multiphoton microscopy causes excitation of endogenously fluorescent macromolecular systems and induces highly specific second harmonic generation signals from non-centrosymmetric macromolecules such as fibrillar collagens. Both these signals can be captured simultaneously to provide spatially resolved 3D structural organization of extracellular matrix as well as the cellular morphologies in their native states.

View Article and Find Full Text PDF

Activated macrophages have been characterized as M1 and M2 according to their inflammatory response pattern. Here we analyzed the M2 marker expression and intracellular signal transduction in the course of cytokine-driven differentiation. We found elevated spontaneous production of the chemokines CCL17, CCL18 and CCL22 and increased expression of CD206 by alveolar macrophages from patients with lung fibrosis.

View Article and Find Full Text PDF

Given the contribution various fibroblast subsets make to wound healing and tissue remodeling, the concept of lung fibroblast heterogeneity is of great interest. However, the mechanisms contributing to this heterogeneity are unknown. To this aim, we compared molecular and biophysical characteristics of fibroblasts concurrently isolated from normal human proximal bronchi (B-FBR) and distal lung parenchyma (P-FBR).

View Article and Find Full Text PDF

Rationale: Airway remodeling in asthma is associated with the accumulation of fibroblasts, the primary cell responsible for synthesis and secretion of extracellular matrix proteins. The process by which the number of fibroblasts increases in asthma is poorly understood, but epithelial-mesenchymal transition (EMT) may play a significant role.

Objectives: To evaluate whether EMT occurs in primary airway epithelial cells (AECs), the mechanisms involved, and if this process is altered in asthmatic AECs.

View Article and Find Full Text PDF

The airway epithelium is the first line of contact with the inhaled external environment and is continuously exposed to and injured by pollutants, allergens, and viruses. However, little is known about epithelial repair and in particular the identity and role of tissue resident stem/progenitor cells that may contribute to epithelial regeneration. The aims of the present study were to identify, isolate, and characterize side population (SP) cells in human tracheobronchial epithelium.

View Article and Find Full Text PDF

In response to transforming growth factor beta1 (TGFbeta) stimulation, fibroblasts modify their integrin repertoire and adhesive capabilities to certain extracellular matrix proteins. Although TGFbeta has been shown to increase the expression of specific alphav integrins, the mechanisms underlying this are unknown. In this study we demonstrate that TGFbeta1 increased both beta3 integrin subunit mRNA and protein levels as well as surface expression of alphavbeta3 in human lung fibroblasts.

View Article and Find Full Text PDF

Objective: In diffuse parenchymal lung diseases, the evolution of pulmonary fibrosis is often devastating and may result in death. In this study the role of CCL18 as a biomarker of disease activity in idiopathic interstitial pneumonias (IIPs) and systemic sclerosis (SSc) with lung involvement was evaluated.

Methods: CCL18 was assessed in supernatants of cultured bronchoalveolar lavage (BAL) cells as well as BAL fluid and serum samples from 43 patients with IIPs, 12 patients with SSc, and 23 healthy control subjects.

View Article and Find Full Text PDF

Background: Recently the immune regulatory role of T cell-derived IL-10 in allergic disease has been extensively studied. In contrast, there is mounting evidence that IL-10 might also have a role in the perpetuation of allergic inflammation and fibrotic remodeling. It has been reported that alternatively (IL-4) activated macrophages (aaMPhi) produce large quantities of IL-10 and lack IL-12 production.

View Article and Find Full Text PDF

Endothelin-1 (ET-1), a G protein-coupled receptor-activating peptide, is increased in airway epithelium, plasma, and bronchoalveolar lavage fluid of asthmatic patients. We hypothesized that ET-1 may contribute to the increased airway smooth muscle mass found in severe asthma by inducing hypertrophy and inhibiting apoptosis of smooth muscle cells. To investigate this hypothesis, we determined that treatment of primary human bronchial smooth muscle cells with ET-1 dose dependently [10(-11)-10(-7) M] inhibited the apoptosis induced by serum withdrawal.

View Article and Find Full Text PDF

The aims of the present study were to characterize the localization of interleukin-18 (IL-18) expression in lung tissue specimens from patients with pulmonary tuberculosis, sarcoidosis and controls, and to determine whether human alveolar epithelial cells type II (AEC-II) are able to generate IL-18 in primary culture. IL-18 was determined using semiquantitative reverse-transcription-PCR and localized in lungs using in situ hybridization. IL-18 protein levels were determined using the enzyme-linked immunosorbent assay and western blot analysis.

View Article and Find Full Text PDF

Rationale: Recently, models of macrophage activation have been revised. Macrophages stimulated with Th2 cytokines have been classified as alternatively activated.

Objectives: This article examines the expression and regulation of CC chemokine ligand 18 (CCL18), a marker of alternative activation, by human alveolar macrophages (AMs).

View Article and Find Full Text PDF

We have previously shown that macrophage infection with Mycobacterium tuberculosis and M. bovis bacillus Calmette-Guérin (BCG) partially inhibits MHC class II surface expression in response to IFN-gamma. The present study examined the nature of class II molecules that do in fact reach the surface of infected cells.

View Article and Find Full Text PDF

The attraction of leukocytes from circulation to inflamed lungs depends on the activation of both the leukocytes and the resident cells within the lung. In this study we determined gene expression and secretion patterns for monocyte chemoattractant protein-1 (MCP-1/CCL2) and T-cell specific CXCR3 agonistic chemokines (Mig/CXCL9, IP-10/CXCL10, and I-TAC/CXCL11) in TNF-alpha-, IFN-gamma-, and IL-1beta-stimulated human alveolar epithelial cells type II (AEC-II). AEC-II constitutively expressed high level of CCL2 mRNA in vitro and in situ , and released CCL2 protein in vitro .

View Article and Find Full Text PDF