Thrombospondin-1 mediates multi-walled carbon nanotube induced impairment of arteriolar dilation

<p>Pulmonary exposure to multi-walled carbon nanotubes (MWCNT) has been shown to disrupt endothelium-dependent arteriolar dilation in the peripheral microcirculation. The molecular mechanisms behind these arteriolar disruptions have yet to be fully elucidated. The secreted matricellular matrix protein thrombospondin-1 (TSP-1) is capable of moderating arteriolar vasodilation by inhibiting soluble guanylate cyclase activity. We hypothesized that TSP-1 may be a link between nanomaterial exposure and observed peripheral microvascular dysfunction. To test this hypothesis, wild-type C57B6J (WT) and TSP-1 knockout (KO) mice were exposed <i>via</i> lung aspiration to 50 μg MWCNT or a Sham dispersion medium control. Following exposure (24 h), arteriolar characteristics and reactivity were measured in the gluteus maximus muscle using intravital microscopy (IVM) coupled with microiontophoretic delivery of acetylcholine (ACh) or sodium nitroprusside (SNP). In WT mice exposed to MWCNT, skeletal muscle TSP-1 protein increased > fivefold compared to Sham exposed, and exhibited a 39% and 47% decrease in endothelium-dependent and -independent vasodilation, respectively. In contrast, TSP-1 protein was not increased following MWCNT exposure in KO mice and exhibited no loss in dilatory capacity. Microvascular leukocyte–endothelium interactions were measured by assessing leukocyte adhesion and rolling activity in third order venules. The WT + MWCNT group demonstrated 223% higher leukocyte rolling compared to the WT + Sham controls. TSP-1 KO animals exposed to MWCNT showed no differences from the WT + Sham control. These data provide evidence that TSP-1 is likely a central mediator of the systemic microvascular dysfunction that follows pulmonary MWCNT exposure.</p

The Sources of Inflammatory Mediators in the Lung after Silica Exposure-1

<p><b>Copyright information:</b></p><p>Taken from "The Sources of Inflammatory Mediators in the Lung after Silica Exposure"</p><p>Environmental Health Perspectives 2004;112(17):1679-1685.</p><p>Published online 16 Aug 2004</p><p>PMCID:PMC1253659.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

The Sources of Inflammatory Mediators in the Lung after Silica Exposure-6

<p><b>Copyright information:</b></p><p>Taken from "The Sources of Inflammatory Mediators in the Lung after Silica Exposure"</p><p>Environmental Health Perspectives 2004;112(17):1679-1685.</p><p>Published online 16 Aug 2004</p><p>PMCID:PMC1253659.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Inflammatory cytokine concentrations in A) BAL fluid and B) blood plasma.

<p>(†P < 0.05 compared to the vehicle control and WC-Co NP exposed groups)</p

Summary of the characteristics of WC-Co NP, including size and elemental composition.

<p>Summary of the characteristics of WC-Co NP, including size and elemental composition.</p

Histology of isolated BAL fluid cells from a representative A) control (vehicle only) rat and B) 500 μg WC-Co NP exposed rat.

<p>Scale bars = 20 μm. (black arrow = alveolar macrophage, AM; arrow head = erythrocyte; dotted arrow = polymorphonuclear leukocyte, PMN; wide arrow = AM with WC-Co NPs)</p

Pulmonary inflammation parameters assessed in the BAL fluid following 24-hr exposure to WC-Co and CeO₂ NPs: A) LDH activity, B) albumin, and C) AM chemiluminescence.

<p>Values presented as mean ± SD. (*P < 0.05, ‡P < 0.001 compared to the vehicle control, and †P < 0.01 compared to WC-Co NP exposed groups)</p

Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure-3

<p><b>Copyright information:</b></p><p>Taken from "Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure"</p><p>Environmental Health Perspectives 2005;114(3):412-419.</p><p>Published online 13 Oct 2005</p><p>PMCID:PMC1392236.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure-7

<p><b>Copyright information:</b></p><p>Taken from "Systemic Microvascular Dysfunction and Inflammation after Pulmonary Particulate Matter Exposure"</p><p>Environmental Health Perspectives 2005;114(3):412-419.</p><p>Published online 13 Oct 2005</p><p>PMCID:PMC1392236.</p><p>This is an Open Access article: verbatim copying and redistribution of this article are permitted in all media for any purpose, provided this notice is preserved along with the article's original DOI.</p

Multiwalled carbon nanotube-induced pulmonary inflammatory and fibrotic responses and genomic changes following aspiration exposure in mice: A 1-year postexposure study

<p>Pulmonary exposure to multiwalled carbon nanotubes (MWCNT) induces an inflammatory and rapid fibrotic response, although the long-term signaling mechanisms are unknown. The aim of this study was to examine the effects of 1, 10, 40, or 80 μg MWCNT administered by pharyngeal aspiration on bronchoalveolar lavage (BAL) fluid for polymorphonuclear cell (PMN) infiltration, lactate dehydrogenase (LDH) activity, and lung histopathology for inflammatory and fibrotic responses in mouse lungs 1 mo, 6 mo, and 1 yr postexposure. Further, a 120-μg crocidolite asbestos group was incorporated as a positive control for comparative purposes. Results showed that MWCNT increased BAL fluid LDH activity and PMN infiltration in a dose-dependent manner at all three postexposure times. Asbestos exposure elevated LDH activity at all 3 postexposure times and PMN infiltration at 1 mo and 6 mo postexposure. Pathological changes in the lung, the presence of MWCNT or asbestos, and fibrosis were noted at 40 and 80 μg MWCNT and in asbestos-exposed mice at 1 yr postexposure. To determine potential signaling pathways involved with MWCNT-associated pathological changes in comparison to asbestos, up- and down-regulated gene expression was determined in lung tissue at 1 yr postexposure. Exposure to MWCNT tended to favor those pathways involved in immune responses, specifically T-cell responses, whereas exposure to asbestos tended to favor pathways involved in oxygen species production, electron transport, and cancer. Data indicate that MWCNT are biopersistent in the lung and induce inflammatory and fibrotic pathological alterations similar to those of crocidolite asbestos, but may reach these endpoints by different mechanisms.</p