Role of the Funder/Sponsor: The Lilly Endowment Inc Physician Scientist Initiative had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Carbon nanotubes (CNT), with their applications in industry and medicine, may lead to new risks to human health. CNT induce a robust pulmonary inflammation and oxidative stress in rodents. Realistic exposures to CNT may occur in conjunction with other pathogenic impacts (microbial infections) and trigger enhanced responses. We evaluated interactions between pharyngeal aspiration of singlewalled CNT (SWCNT) and bacterial pulmonary infection of C57BL/6 mice with Listeria monocytogenes (LM). Mice were given SWCNT (0, 10, and 40 mg/mouse) and 3 days later were exposed to LM (10 3 bacteria/ mouse). Sequential exposure to SWCNT/LM amplified lung inflammation and collagen formation. Despite this robust inflammatory response, SWCNT pre-exposure significantly decreased the pulmonary clearance of LM-exposed mice measured 3 to 7 days after microbial infection versus PBS/LM-treated mice. Decreased bacterial clearance in SWCNT-pre-exposed mice was associated with decreased phagocytosis of bacteria by macrophages and a decrease in nitric oxide production by these phagocytes. Pre-incubation of naïve alveolar macrophages with SWCNT in vitro also resulted in decreased nitric oxide generation and suppressed phagocytizing activity toward LM. Failure of SWCNT-exposed mice to clear LM led to a continued elevation in nearly all major chemokines and acute phase cytokines into the later course of infection. In SWCNT/LM-exposed mice, bronchoalveolar lavage neutrophils, alveolar macrophages, and lymphocytes, as well as lactate dehydrogenase level, were increased compared with mice exposed to SWCNT or LM alone. In conclusion, enhanced acute inflammation and pulmonary injury with delayed bacterial clearance after SWCNT exposure may lead to increased susceptibility to lung infection in exposed populations.

Aerosol particles expelled during human coughs are a potential pathway for infectious disease transmission. However, the importance of airborne transmission is unclear for many diseases. To better understand the role of cough aerosol particles in the spread of disease and the efficacy of different types of protective measures, we constructed a cough aerosol simulator that produces a humanlike cough in a controlled environment. The simulated cough has a 4.2 l volume and is based on coughs recorded from influenza patients. In one configuration, the simulator produces a cough aerosol containing particles from 0.1 to 100 µm in diameter with a volume median diameter (VMD) of 8.5 µm and a geometric standard deviation (GSD) of 2.9. In a second configuration, the cough aerosol has a size range of 0.1-30 µm, a VMD of 3.4 µm, and a GSD of 2.3. The total aerosol volume expelled during each cough is 68 µl. By generating a controlled and reproducible artificial cough, the simulator allows us to test different ventilation, disinfection, and personal protection scenarios. The system can be used with live pathogens, including influenza virus, which allows isolation precautions used in the healthcare field to be tested without risk of exposure for workers or patients. The information gained from tests with the simulator will help to better understand the transmission of infectious diseases, develop improved techniques for infection control, and improve safety for healthcare workers and patients.

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Few studies have quantified the dispersion of potentially infectious bioaerosols produced by patients in the health care environment and the exposure of health care workers to these particles. Controlled studies are needed to assess the spread of bioaerosols and the efficacy of different types of respiratory personal protective equipment (PPE) in preventing airborne disease transmission. An environmental chamber was equipped to simulate a patient coughing aerosol particles into a medical examination room, and a health care worker breathing while exposed to these particles. The system has three main parts: (1) a coughing simulator that expels an aerosol-laden cough through a head form; (2) a breathing simulator with a second head form that can be fitted with respiratory PPE; and (3) aerosol particle counters to measure concentrations inside and outside the PPE and at locations throughout the room. Dispersion of aerosol particles with optical diameters from 0.3 to 7.5 μm was evaluated along with the influence of breathing rate, room ventilation, and the locations of the coughing and breathing simulators. Penetration of cough aerosol particles through nine models of surgical masks and respirators placed on the breathing simulator was measured at 32 and 85 L/min flow rates and compared with the results from a standard filter tester. Results show that cough-generated aerosol particles spread rapidly throughout the room, and that within 5 min, a worker anywhere in the room would be exposed to potentially hazardous aerosols. Aerosol exposure is highest with no personal protective equipment, followed by surgical masks, and the least exposure is seen with N95 FFRs. These differences are seen regardless of breathing rate and relative position of the coughing and breathing simulators. These results provide a better understanding of the exposure of workers to cough aerosols from patients and of the relative efficacy of different types of respiratory PPE, and they will assist investigators in providing research-based recommendations for effective respiratory protection strategies in health care settings.

BackgroundCellulose-based materials have been used for centuries to manufacture different goods derived from forestry and agricultural sources. In the growing field of nanocellulose applications, its uniquely engineered properties are instrumental for inventive products coming to competitive markets. Due to their high aspect ratio and stiffness, it is speculated that cellulose nanocrystals (CNC) may cause similar pulmonary toxicity as carbon nanotubes and asbestos, thus posing a potential negative impact on public health and the environment.MethodsThe present study was undertaken to investigate the pulmonary outcomes induced by repeated exposure to respirable CNC. C57BL/6 female and male mice were exposed by pharyngeal aspiration to CNC (40 μg/mouse) 2 times a week for 3 weeks. Several biochemical endpoints and pathophysiological outcomes along with gene expression changes were evaluated and compared in the lungs of male and female mice.ResultsExposure to respirable CNC caused pulmonary inflammation and damage, induced oxidative stress, elevated TGF-β and collagen levels in lung, and impaired pulmonary functions. Notably, these effects were markedly more pronounced in females compared to male mice. Moreover, sex differences in responses to pulmonary exposure to CNC were also detected at the level of global mRNA expression as well as in inflammatory cytokine/chemokine activity.ConclusionsOverall, our results indicate that there are considerable differences in responses to respirable CNC based on gender with a higher pulmonary toxicity observed in female mice.Electronic supplementary materialThe online version of this article (doi:10.1186/s12989-016-0140-x) contains supplementary material, which is available to authorized users.

Muscle damage due to stretch-shortening cycles (i.e., cyclic eccentric/concentric muscle actions) is one of the major concerns in sports and occupational related activities. Mechanical responses of whole muscle have been associated with damage in neural motor units, in connective tissues, and the force generation mechanism. The objective of this study was to introduce a new method to quantify the real-time changes in skeletal muscle forces of rats during injurious stretch-shortening cycles. Male Sprague Dawley rats ( n=24) were selected for use in this study. The dorsi flexor muscle group was exposed to either 150 stretch-shortening cycles ( n=12) or 15 isometric contractions ( n=12) in vivo using a dynamometer and electrical stimulation. Muscle damage after exposure to stretch-shortening cycles was verified by the non-recoverable force deficit at 48 h and the presence of myofiber necrosis. Variations of the dynamic forces during stretch-shortening cycles were analyzed by decomposing the dynamic force signature into peak force ( F(peak)), minimum force ( F(min)), average force ( F(mean)), and cyclic force ( F(a)). After the 15th set of stretch-shortening cycles, the decrease in the stretch-shortening parameters, F(peak), F(min), F(mean), and F(a), was 50% ( P<0.0001), 26% ( P=0.0055), 68% ( P<0.0001), and 50% ( P<0.0001), respectively. Our results showed that both isometric contractions and stretch-shortening cycles induce a reduction in the isometric force. However, the force reduction induced by isometric contractions fully recovered after a break of 48 h while that induced by stretch-shortening cycles did not. Histopathologic assessment of the tibialis anterior exposed to stretch-shortening cycles showed significant myofiber degeneration and necrosis with associated inflammation, while muscles exposed to isometric contractions showed no myofiber degeneration and necrosis, and limited inflammation. Our results suggest that muscle damage can be identified by the non-recoverable isometric force decrement and also by the variations in the dynamic force signature during stretch-shortening cycles.

Several lines of evidence indicate that exposure to nanoparticles (NPs) is able to modify airway immune responses, thus facilitating the development of respiratory diseases. Graphene oxide (GO) is a promising carbonaceous nanomaterial with unique physicochemical properties, envisioned for a multitude of medical and industrial applications. In this paper, we determined how exposure to GO modulates the allergic pulmonary response. Using a murine model of ovalbumin (OVA)-induced asthma, we revealed that GO, given at the sensitization stage, augmented airway hyperresponsiveness and airway remodeling in the form of goblet cell hyperplasia and smooth muscle hypertrophy. At the same time, the levels of the cytokines IL-4, IL-5, and IL-13 were reduced in broncho-alveolar lavage (BAL) fluid in GO-exposed mice. Exposure to GO during sensitization with OVA decreased eosinophil accumulation and increased recruitment of macrophages in BAL fluid. In line with the cytokine profiles, sensitization with OVA in the presence of GO stimulated the production of OVA-specific IgG2a and down-regulated the levels of IgE and IgG1. Moreover, exposure to GO increased the macrophage production of the mammalian chitinases, CHI3L1 and AMCase, whose expression is associated with asthma. Finally, molecular modeling has suggested that GO may directly interact with chitinase, affecting AMCase activity, which has been directly proven in our studies. Thus, these data show that GO exposure attenuates Th2 immune response in a model of OVA-induced asthma, but leads to potentiation of airway remodeling and hyperresponsiveness, with the induction of mammalian chitinases.