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Dosimetry provides information linking environmental exposures to sites of deposition, removal from these sites, and translocation of deposited materials. Dosimetry also aids in extrapolating laboratory animal and in vitro data to humans. Recent progress has shed light on: properties of particles in relation to their fates in the body; influence of age, gender, body size, and lung diseases on inhaled particle doses; particle movement to the brain via the olfactory nerves; and particle deposition hot spots in the respiratory tract. Ultrafine size has emerged as an important dosimetric characteristic. Particle count, composition, and surface properties are recognized as potentially important toxicology-related considerations. Differences in body size influence airway sizes, inhaled particle deposition, specific ventilation, and specific doses (e.g. per unit body mass). Related to body size, age, gender, species, and strain are also dosimetric considerations. Diseases, such as chronic obstructive pulmonary disease (COPD) and bronchitis, produce uneven doses within the respiratory tract. Traditional concepts of the translocation and clearance of deposited particles have been challenged. Ultrafine particles can translocate to the brain via olfactory nerves, and from the lung to other organs. The clearance rates of particles from tracheobronchial airways are slowed by respiratory tract infections, but newer evidence implies that slow particle clearance from this region also exists in healthy lungs. Finally, hot spots of particle deposition are seen in hollow models, lung tissue, and dosimetric simulations. Local doses to groups of epithelial cells can be much greater than those to surrounding cells. The new insights challenge dosimetry scientists.

The determination of the dose of inhaled aerosol particles in animal subjects is not a trivial exercise. In its simplest form, the dose is the amount (particle number, mass or other relevant metric) that deposits in the respiratory tract. The amount deposited will depend on the aerosol particle sizes (e.g. the aerodynamic diameter size distribution), the duration of exposure, the exposure system's delivery efficiency, the subject's ventilation rate, the species and strain, and other factors. Similarly, species differences in the clearance rates of deposited particles will influence the time integrated particle doses. In practice, particle doses are estimated using mathematical models, previous experimental dosimetry data, tracers of the inhaled particles and biomarkers of exposure. With care, desired aerosol doses can be achieved and documented.

Cervical cancer (CC) is women's fourth most common cancer worldwide. A worrying increase in CC rates in Hispanics suggests that besides Human papillomavirus infections, there may be other cofactors included in the epithelial microenvironment that could play a role in promoting the disease. We hypothesized that the cervical microbiome and the epithelial microenvironment favoring inflammation is conducive to disease progression in a group of Hispanics attending gynecology clinics in Puerto Rico. Few studies have focused on the joint microbiota and cytokine profile response in Hispanics outside the US, especially regarding the development of precancerous lesions. We aimed to investigate the relationship between the cervicovaginal microbiome and inflammation in Hispanic women living in PR while considering cervical dysplasia and HPV genotype risk. Cervical samples collected from 91 participants coming to gynecology clinics in San Juan, underwent 16S rRNA genes (V4 region) profiling, and cytokines were measured using Luminex MAGPIX technology. Cytokines were grouped as inflammatory (IL-1β, TNFα, IFNγ, IL-6), anti-inflammatory (IL- 4, IL-10, TGFβ1), and traffic-associated (IL-8, MIP1a, MCP1, IP10). They were related to microbes via an inflammation scoring index based on the quartile and tercile distribution of the cytokine's concentration. We found significant differences in the diversity and composition of the microbiota according to HPV type according to carcinogenic risk, cervical disease, and cytokine abundance. Community State Types (CSTs) represents a profile of microbial communities observed within the vaginal microbiome ecological niche, and Lactobacillus-depleted CST IV had ~ 90% dominance in participants with high-grade squamous intraepithelial lesions and high-risk HPV. The increasing concentration of pro-inflammatory cytokines was associated with a decrease in L. crispatus. In contrast, dysbiosis-associated bacteria such as Gardnerella, Prevotella, Atopobium concomitantly increased with pro-inflammatory cytokines. Our study highlights that the cervical microbiota of Hispanics living in Puerto Rico is composed mostly of diverse CST profiles with decreased Lactobacillus and is associated with a higher pro-inflammatory environment. The joint host-microbe interaction analyses via cytokine and microbiota profiling have very good translational potential. [ABSTRACT FROM AUTHOR]

Motor vehicle exhaust emissions are known to exacerbate asthma and other respiratory diseases. Several studies have demonstrated significant associations between living near highly trafficked roadways and increased incidence of asthma and increased severity of asthma-related symptoms, medication usage, and physician visits. This study tested the hypotheses that (1) exposure to particulate matter (PM) near a heavily trafficked Los Angeles freeway would enhance inflammatory and allergic responses in ovalbumin (OVA)-sensitized BALB/c mice compared to sensitized, clean air controls, and (2) there would be differences in response at two distances downwind of heavily traveled freeways because of greater toxicity of PM closest to the freeway. An ambient particle concentrator was used to expose ovalbumin (OVA)-treated BALB/c mice to purified air, to concentrated fine ambient particles, and to concentrated ultrafine airborne particles (CAPs) at 2 distances, 50 m and 150 m, downwind of a roadway that is impacted by emissions from both heavy-duty diesel and light duty gasoline vehicles. Tissues and biological fluids from the mice were analyzed after exposures for 5 days/wk in 2 consecutive weeks. The biomarkers of allergic or inflammatory responses that were assessed included cytokines released by Type 2 T-helper cells (interleukin [IL]-5 and IL-13), OVA-specific immunoglobulin E (IgE), OVA-specific immunoglobulin G1 (IgG1), and pulmonary infiltration of polymorphonuclear leukocytes and eosinophils. IL-5 and IgG1 were significantly increased in mice exposed to CAPs 50 m downwind of the road, compared to responses in mice exposed to purified air, providing evidence of allergic response. No significant increases in allergy-related responses were observed in mice exposed to CAPs 150 m downwind of the road. The biological responses at the 50-m site were significantly associated with organic and elemental carbon components of fine and ultrafine particles (p ≤ .05). The primary source of these contaminants at the roadway sites was motor vehicle emissions, suggesting that particulate matter from motor vehicle fuel combustion could exert adjuvant effects and promote the development of allergic airway diseases. [ABSTRACT FROM AUTHOR]

Heart disease is a major killer in western societies; coronary artery disease and atherosclerosis are important contributors to this mortality. Atherosclerosis in mice with a deleted apoE gene (apoE −/−) is accelerated by exposure to ambient ultrafine particles (UFP) which are particles smaller than 180 nm in diameter. UFP contain organic components that are pro-oxidant and may cause or aggravate heart disease. Could removal of these organic constituents mitigate adverse cardiovascular effects? ApoE −/− mice were exposed to concentrated UFP (CAP), CAP from which organic constituents were removed by thermal denuding (deCAP) or purified air (controls) for 5 hr/day, 4 days/week for 8 weeks. Heart rate (HR), heart rate variability (HRV), biomarkers of oxidative stress and the sizes of arterial plaques were measured. Adverse effects were seen in CAP-exposed mice (increased size of arterial plaque, increased oxidative stress and decreased HRV, compared to controls). Adverse effects were not observed in deCAP-exposed mice. Removal of organic constituents from ambient particles resulted in significant reduction of toxic cardiovascular effects of air pollution exposure. [ABSTRACT FROM AUTHOR]

• Status epilepticus (SE) results in complement hyperactivation and memory deficits. • C1 esterase inhibitor (C1-INH) accelerates weight recovery following SE. • C1-INH does not attenuate SE-induced memory deficits. • SE-induced increases in C3 are inversely correlated to loss of synaptic proteins. Status epilepticus (SE) is a prolonged and continuous seizure that lasts for at least 5 min. An episode of SE in a healthy system can lead to the development of spontaneous seizures and cognitive deficits which may be accompanied by hippocampal injury and microgliosis. Although the direct mechanisms underlying the SE-induced pathophysiology remain unknown, a candidate mechanism is hyperactivation of the classical complement pathway (C1q-C3 signaling). We recently reported that SE triggered an increase in C1q-C3 signaling in the hippocampus that closely paralleled cognitive decline. Thus, we hypothesized that blocking activation of the classical complement pathway immediately after SE may prevent the development of SE-induced hippocampal-dependent learning and memory deficits. Because C1 esterase inhibitor (C1-INH) negatively regulates activation of the classical complement pathway, we used this drug to test our hypothesis. Two groups of male rats were subjected to 1 hr of SE with pilocarpine (280–300 mg/kg, i.p.), and treated with either C1-INH (SE+C1-INH, 20 U/kg, s.c.) or vehicle (SE+veh) at 4, 24, and 48 h after SE. Control rats were treated with saline. Body weight was recorded for up to 23 days after SE. At two weeks post SE, recognition and spatial memory were determined using Novel Object Recognition (NOR) and Barnes maze (BM), respectively, as well as locomotion and anxiety-like behaviors using Open Field (OF). Histological and biochemical methods were used to measure hippocampal injury including cell death, microgliosis, and inflammation. One day after SE, both SE groups had a significant loss of body weight compared to controls (p <0.05). By day 14, the weight of SE+C1-INH rats was significantly higher than SE+veh rats (p <0.05), and was not different from controls (p >0.05). At 14 days post-SE, SE+C1-INH rats displayed higher mobility (distance travelled and average speed, p <0.05) and had reduced anxiety-like behaviors (outer duration, p <0.05) than control or SE+veh rats. In NOR, control rats spent significantly more time exploring the novel object vs. the familiar (p <0.05), while rats in both SE groups spent similar amount of time exploring both objects. During days 1–4 of BM training, the escape latency of the control group significantly decreased over time (p <0.05), whereas that of the SE groups did not improve (p >0.05). Compared to vehicle-treated SE rats, SE+C1-INH rats had increased levels of C3 and microglia in the hippocampus, but lower levels of caspase-3 and synaptic markers. These findings suggest that acute treatment with C1-INH after SE may have some protective, albeit limited, effects on the physiological recovery of rats' weight and some anxiolytic effects, but does not attenuate SE-induced deficits in hippocampal-dependent learning and memory. Reduced levels of caspase-3 suggest that treatment with C1-INH may protect against cell death, perhaps by regulating inflammatory pathways and promoting phagocytic/clearance pathways. [ABSTRACT FROM AUTHOR]

Importance: Sepsis is the consequence of a systemic bacterial infection that exacerbates the immune cell's activation via bacterial products, resulting in the augmented release of inflammatory mediators. A critical factor in the pathogenesis of sepsis is the primary component of the outer membrane of Gram-negative bacteria known as lipopolysaccharide (LPS), which is sensed by TLR4. For this reason, scientists have aimed to develop antagonists able to block TLR4 and, thereby the cytokine storm. We report here that a mixture of mu-class isoforms from the F. hepatica GST protein family administered intraperitoneally 1 h prior to a lethal LPS injection can modulate the dynamics and abundance of large peritoneal macrophages in the peritoneal cavity of septic mice while significantly suppressing the LPS-induced cytokine storm in a mouse model of septic shock. These results suggest that native F. hepatica glutathione S-transferase is a promising candidate for drug development against endotoxemia and other inflammatory diseases., Competing Interests: The authors declare no conflict of interest.

Due to their phylogenetic proximity to humans, nonhuman primates (NHPs) are considered an adequate choice for a basic and preclinical model of sepsis. Gram-negative bacteria are the primary causative of sepsis. During infection, bacteria continuously release the potent toxin lipopolysaccharide (LPS) into the bloodstream, which triggers an uncontrolled systemic inflammatory response leading to death. Our previous research has demonstrated in vitro and in vivo using a mouse model of septic shock that Fh15, a recombinant variant of the Fasciola hepatica fatty acid binding protein, acts as an antagonist of Toll-like receptor 4 (TLR4) suppressing the LPS-induced proinflammatory cytokine storm. The present communication is a proof-of concept study aimed to demonstrate that a low-dose of Fh15 suppresses the cytokine storm and other inflammatory markers during the early phase of sepsis induced in rhesus macaques by intravenous (i.v.) infusion with lethal doses of live Escherichia coli. Fh15 was administered as an isotonic infusion 30 min prior to the bacterial infusion. Among the novel findings reported in this communication, Fh15 (i) significantly prevented bacteremia, suppressed LPS levels in plasma, and the production of C-reactive protein and procalcitonin, which are key signatures of inflammation and bacterial infection, respectively; (ii) reduced the production of proinflammatory cytokines; and (iii) increased innate immune cell populations in blood, which suggests a role in promoting a prolonged steady state in rhesus macaques even in the presence of inflammatory stimuli. This report is the first to demonstrate that a F. hepatica -derived molecule possesses potential as an anti-inflammatory drug against sepsis in an NHP model. IMPORTANCE Sepsis caused by Gram-negative bacteria affects 1.7 million adults annually in the United States and is one of the most important causes of death at intensive care units. Although the effective use of antibiotics has resulted in improved prognosis of sepsis, the pathological and deathly effects have been attributed to the persistent inflammatory cascade. There is a present need to develop anti-inflammatory agents that can suppress or neutralize the inflammatory responses and prevent the lethal consequences of sepsis. We demonstrated here that a small molecule of 14.5 kDa can suppress the bacteremia, endotoxemia, and many other inflammatory markers in an acute Gram-negative sepsis rhesus macaque model. These results reinforce the notion that Fh15 constitutes an excellent candidate for drug development against sepsis.