Innate immune activation by inhaled lipopolysaccharide, independent of oxidative stress, exacerbates silica-induced pulmonary fibrosis in mice

Acute exacerbations of pulmonary fibrosis are characterized by rapid decrements in lung function. Environmental factors that may contribute to acute exacerbations remain poorly understood. We have previously demonstrated that exposure to inhaled lipopolysaccharide (LPS) induces expression of genes associated with fibrosis. To address whether exposure to LPS could exacerbate fibrosis, we exposed male C57BL/6 mice to crystalline silica, or vehicle, followed 28 days later by LPS or saline inhalation. We observed that mice receiving both silica and LPS had significantly more total inflammatory cells, more whole lung lavage MCP-1, MIP-2, KC and IL-1β, more evidence of oxidative stress and more total lung hydroxyproline than mice receiving either LPS alone, or silica alone. Blocking oxidative stress with N-acetylcysteine attenuated whole lung inflammation but had no effect on total lung hydroxyproline. These observations suggest that exposure to innate immune stimuli, such as LPS in the environment, may exacerbate stable pulmonary fibrosis via mechanisms that are independent of inflammation and oxidative stress. © 2012 Brass et al

Validation of Ultrasound Super-Resolution Imaging of Vasa Vasorum in Rabbit Atherosclerotic Plaques

Acute coronary syndromes and strokes are mainly caused by atherosclerotic plaque (AP) rupture. Abnormal increase of vasa vasorum (VV) is reported as a key evidence of plaque progression and vulnerability. However, due to their tiny size, it is still challenging to noninvasively identify VV near the major vessels. Ultrasound super resolution (USR), a technique that provides high spatial resolution beyond the acoustic diffraction limit, demonstrated an adequate spatial resolution for VV detection in early studies. However, a thorough validation of this technology in the plaque model is particularly needed in order to continue further extended preclinical studies. In this letter, we present an experiment protocol that verifies the USR technology for VV identification with subsequent histology and ex vivo micro-computed tomography ( \mu CT). Deconvolution-based USR imaging was applied on two rabbits to identify the VV near the AP in the femoral artery. Histology and ex vivo \mu CT imaging were performed on excised femoral tissue to validate the USR technique both pathologically and morphologically. This established validation protocol could facilitate future extended preclinical studies toward the clinical translation of USR imaging for VV identification. © IEEE.1

Evaluation of the pharmacokinetics, dosimetry, and therapeutic efficacy for the α-particle-emitting transarterial radioembolization (αTARE) agent [225Ac]Ac-DOTA-TDA-Lipiodol® against hepatic tumors

Abstract Background The liver is a common site for metastatic disease for a variety of cancers, including colorectal cancer. Both primary and secondary liver tumors are supplied through the hepatic artery while the healthy liver is supplied by the portal vein. Transarterial radioembolization (TARE) using yttrium-90 glass or resin microspheres have shown promising results with reduced side-effects but have similar survival benefits as chemoembolization in patients with hepatocellular carcinoma (HCC). This highlights the need for new novel agents against HCC. Targeted alpha therapy (TAT) is highly potent treatment due to the short range (sparing adjacent normal tissue), and densely ionizing track (high linear energy transfer) of the emitted α-particles. The incorporation of α-particle-emitting radioisotopes into treatment of HCC has been extremely limited, with our recent publication pioneering the field of α-particle-emitting TARE (αTARE). This study focuses on an in-depth evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as an effective therapeutic agent against HCC regarding pharmacokinetics, dosimetry, stability, and therapeutic efficacy. Results [225Ac]Ac-DOTA-TDA was shown to be a highly stable with bench-top stability at ≥ 95% radiochemical purity (RCP) over a 3-day period and serum stability was ≥ 90% RCP over 5-days. The pharmacokinetic data showed retention in the tumor of [225Ac]Ac-DOTA-TDA-Lipiodol® and clearance through the normal organs. In addition, the tumor and liver acted as suppliers of the free daughters, which accumulated in the kidneys supplied via the blood. The dose limiting organ was the liver, and the estimated maximum tolerable activity based on the rodents whole-body weight: 728–3641 Bq/g (male rat), 396–1982 Bq/g (male mouse), and 453–2263 Bq/g (female mouse), depending on an RBE-value (range 1–5). Furthermore, [225Ac]Ac-DOTA-TDA-Lipiodol® showed significant improvement in survival for both the male and female mice (median survival 47-days) compared with controls (26-days untreated, and 33–35-days Lipiodol® alone). Conclusions This study shows that [225Ac]Ac-DOTA-TDA-Lipiodol® is a stable compound allowing for centralized manufacturing and distribution world-wide. Furthermore, the result of this study support the continue development of evaluation of the αTARE-agent [225Ac]Ac-DOTA-TDA-Lipiodol® as a potential treatment option for treating hepatic tumors

Histology immediately after the end of inhalation challenge.

<p>(A) Saline-Saline; (B) Silica-Saline; (C) Saline-LPS; and (D) Silica-LPS exposed mice immediately after the end of either saline or LPS inhalation challenge. n = 6/group. Images were taken in anatomically comparable regions of the lung at 5× (main images) or 20× (Inset in panel D) magnification. Bar = 100 microns.</p

Whole lung lavage immediately after and 21 days after the end of inhalation challenge.

<p>(A) Total cells×10⁵; (B) total macrophages×10⁵; (C) total neutrophils×10⁵; and total lymphocytes×10⁵. Data are presented as Mean + SEM and are representative of two such experiments. n = 6/group. * p<0.05 LPS vs. Saline (significant difference due to inhalation challenge); # p<0.05 Silica vs. Saline (significant difference due to silica instillation or combined Silica and LPS).</p

Whole lung cytokines immediately after the end of inhalation challenge in mice treated with drinking water alone or drinking water supplemented with 2 mg/ml NAC during LPS exposure.

<p>Total (A) MCP-1; (B) MIP-2; (C) KC; and (D) IL-1β in whole lung lavage. Data are presented as Mean + SEM. n = 8/group. * p<0.05 LPS vs. Saline (significant difference due to inhalation challenge); # p<0.05 Silica vs. Saline (significant difference due to silica instillation or combined Silica and LPS).</p