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Following percutaneous exposure to the nerve agent VX, the remaining intact agent within the skin after decontamination is of great concern. Consequently, this leads to prolonged agent release to the blood circulation resulting in sustained intoxication, which may complicate the medical management. The decontamination procedure used should therefore possess the ability for agent removal both on and within the skin. The efficacy of three decontamination procedures was evaluated by measuring VX and the primary degradation product ethyl methyl phosphonic acid (EMPA) penetrated through human skin and the amount remaining within the skin.Decontamination was initiated 5 min post-exposure to VX on human dermatomed skin. Experiments were conducted using anIn control experiments without decontamination, higher amounts of VX were recovered in the deeper layers of skin compared to EMPA, which was primarily located in theEfficient skin decontamination of VX requires skin decontaminants reaching deeper layers of the skin, and that both absorption and degradation properties are important. In addition, the "wash-in" effect by using soapy water may enhance VX release to the blood circulation.

Metal-organic frameworks (MOFs) have shown promising properties for removal of chemical warfare agents, in particular for material decontamination and functionalized fabrics. The MOF-properties could also be beneficial for skin decontamination, especially when exposed to highly toxic and low volatile nerve agents. In such exposures, efficient decontamination is crucial for adequate medical management. In the present study, seven zirconium-based MOFs were evaluated for their ability to degrade VX and subsequently tested in vitro for decontamination of VX on human dermatomed skin. Of the MOFs evaluated, MOF-808 showed the greatest ability to degrade VX in an alkaline buffer with complete degradation of VX within 5 min. PCN-777, Zr-NDC and NU-1000 displayed degradation half-lives of approximately 10 min. When including MOF-808 in a skin friendly carrier with slightly acidic pH, a decreased agent degradation rate was observed, requiring over 24 h to reach complete degradation. In skin decontamination experiments, MOF-808 enhanced the efficacy compared to the carrier alone, essentially by improved agent absorption. Adding MOF-808 to Reactive Skin Decontamination Lotion (RSDL) did not improve the high effectiveness of RSDL alone. The present study showed that including MOF in skin decontamination lotions could be beneficial. Further studies should include optimizing the particulates and formulations.

In mass casualty incidents including hazardous chemical skin exposure, decontamination is the primary intervention to avoid systemic uptake of the toxic compound. The protocol needs to be both simple and efficient to enable a rapid response and avoid delay of patient management. In the present study, decontamination strategies included in the initial operational response were evaluated following human skin exposure in vitro to four different contaminants. Results demonstrated that the efficacy of selected decontamination procedures was highly dependent on the chemical contaminant used. Dry removal of the sulfur mustard simulant methyl salicylate prior to wet decontamination was found beneficial compared to wet decontamination alone. Rapidly initiated wet decontamination was more efficient compared to dry and wet removal of the industrial chemical 2-butoxyethanol and the nerve agent tabun. Following VX-exposure, all wet decontamination procedures resulted in increased agent penetration compared to the control. In conclusion, challenges in establishing simple and efficient decontamination procedures for a broad-spectrum of chemicals have been demonstrated. The impact of including a dry removal step during decontamination was evidently agent specific. Despite the variation in efficacy, immediately initiated dry removal may facilitate patient management until wet decontamination resources are available and to reduce the risk of secondary contamination.

Skin decontamination in cold weather temperatures might be challenging due to the aggravating circumstances. However, no information is available on the efficacy of commonly used procedures in winter conditions. Therefore, the efficacy of the reactive skin decontamination lotion (RSDL) and soapy water decontamination following skin exposure to the nerve agent VX was evaluated at three ambient air temperatures (-5°C, -15°C and room temperature). Experiments were performed in vitro using human dermatomed skin. The ability of RSDL to degrade VX at the three different air temperatures was separately evaluated. The ambient air temperature in experiments without decontamination did not influence the penetration rate of VX through skin. RSDL decontamination was highly efficient in removing VX from skin when performed in all three ambient temperatures, despite the slower agent degradation rate of VX at the lower temperatures. Decontamination with soapy water at RT resulted in an increased skin penetration of VX compared with the control without decontamination; however, in colder temperatures the VX skin penetration was similar to the corresponding control without decontamination. At RT, dry removal prior to washing with soapy water did not improve decontamination of VX compared with washing solely with soapy water. This study demonstrated high efficacy of RSDL decontamination following skin exposure to VX also at cold temperatures. The previously reported 'wash-in' effect of soapy water on VX skin penetration was reduced at cold temperatures. Altogether, this study found a scientific basis to establish guidelines for skin decontamination of chemical casualties at cold weather temperatures.

Background Differences in the expression of regulatory T cells (Tregs) have been suggested to explain why some smokers develop COPD and some do not. Upregulation of Tregs in response to smoking would restrain airway inflammation and thus the development of COPD; while the absense of such upregulation would over time lead to chronic inflammation and COPD. We hypothesized that—among COPD patients—the same mechanism would affect rate of decline in lung function; specifically, that a decreased expression of Tregs would be associated with a more rapid decline in FEV1. Methods Bronchoscopy with BAL was performed in 52 subjects recruited from the longitudinal OLIN COPD study; 12 with COPD and a rapid decline in lung function (loss of FEV1 ≥ 60 ml/year), 10 with COPD and a non-rapid decline in lung function (loss of FEV1 ≤ 30 ml/year), 15 current and ex-smokers and 15 non-smokers with normal lung function. BAL lymphocyte subsets were determined using flow cytometry. Results The proportions of Tregs with regulatory function (FoxP3+/CD4+CD25bright) were significantly lower in COPD subjects with a rapid decline in lung function compared to those with a non-rapid decline (p = 0.019). This result was confirmed in a mixed model regression analysis in which adjustments for inhaled corticosteroid usage, smoking, sex and age were evaluated. No significant difference was found between COPD subjects and smokers or non-smokers with normal lung function. Conclusions COPD subjects with a rapid decline in lung function had lower proportions of T cells with regulatory function in BAL fluid, suggesting that an inability to suppress the inflammatory response following smoking might lead to a more rapid decline in FEV1. Trial registration Clinicaltrials.gov identifier NCT02729220

Early initiated decontamination is demonstrated to be crucial to avoid systemic effects of highly toxic and low volatile agents exposed on the skin. Skin decontamination can be performed by simple procedures, such as washing with soap and water, or by using advanced decontamination products containing absorption and agent degradation properties. Reactive Skin Decontamination Lotion (RSDL) has demonstrated high efficacy to remove nerve agents from the skin. However, contrary to the current operational recommendations, experimental studies have shown that prolonged skin contact time of RSDL is important for efficient decontamination of VX. In the present study, several RSDL-protocols were evaluated for the efficacy to remove neat VX from human skin in vitro. The decontamination efficacies of the RSDL-procedures were compared with the efficacy of the simple procedure of washing off the skin with soapy water. The RSDL-protocols containing repeated swabbing with the sponge and a 10 min skin contact time of RSDL-lotion demonstrated the greatest decontamination efficacy of all procedures evaluated. Repeating the protocol 2 h after the initial decontamination step resulted in a transient increased skin penetration of remaining intact agent on skin and was followed by rapidly declined agent penetration rate. Decontamination performed with soapy water significantly increased agent amounts penetrating skin, most likely caused by skin hydration and agent dilution. In conclusion, a slightly extended procedure for RSDL-decontamination showed improved efficacy and is therefore recommended for removal of nerve agents from the skin. In addition, it is of highest importance that skin decontamination of nerve agents should consist of procedures using low water content.

Inhalation of sulfur dioxide (SOFemale Sprague-Dawley rats exposed to SOBoth treatment approaches significantly reduced the total leukocyte response in bronchoalveolar lavage fluid and suppressed pulmonary edema. In contrast to DEX-treatment, PFD-treatment reduced the methacholine-induced AHR to almost control levels and partially suppressed the acute mucosal damage whereas multiple DEX-treatment was the only treatment that reduced collagen formation in lung tissue.To enable an accurate extrapolation of animal derived data to humans, a detailed understanding of the underlying mechanisms of the injury, and potential treatment options, is needed. The findings of the present study suggest that treatments with the capability to reduce both AHR, the inflammatory response, and fibrosis are needed to achieve a comprehensive mitigation of the acute lung injury caused by SO

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. alpha-Fe2O3 NPs were synthesized, characterized and tested in a model for toxicity utilizing human whole blood without added anticoagulant. MALDI-TOF of the corona was performed and activation markers for plasma cascade systems (complement, contact and coagulation systems), platelet consumption and release of growth factors, MPO, and chemokine/cytokines from blood cells were analyzed. The coronas formed on the pristine alpha-Fe2O3 NPs contained contact system proteins and they induced massive activation of the contact (kinin/kallikrein) system, as well as thrombin generation, platelet activation, and release of two pro-angiogeneic growth factors: platelet-derived growth factor and vascular endothelial growth factor, whereas complement activation was unaffected. The alpha-Fe2O3 NPs exhibited a noticeable toxicity, with kinin/kallikrein activation, which may be associated with hypotension and long-term angiogenesis in vivo, with implications for cancer, arteriosclerosis and pulmonary disease. Joint and equal contribution to senior authorship by Kristina N. Ekdahl, Padideh Davoodpour and Bo Nilsson

Inhalation of chlorine (Cl2) may cause oxidative acute lung injury (ALI) characterized by pulmonary edema, pneumonitis, and hyperreactive airways. The aim of the study was to identify possible biomarkers for Cl2-induced ALI. Female BALB/c mice were exposed to Cl2 for 15min using two protocols 1) concentration-dependent response (25-200ppm) and 2) time-kinetics (2h-14days post-exposure). Exposure to 50-200ppm Cl2 caused a concentration-dependent inflammatory response with increased expression of IL-1β, IL-6 and CXCL1/KC in bronchoalveolar lavage fluid 2-6h after exposure which was followed by increased lung permeability and a neutrophilic inflammation 12-24h post-exposure. The early inflammatory cytokine response was associated with a clear but transient increase of 8-isoprostane, a biomarker for oxidative stress, with its maximum at 2h after exposure. An increase of 8-isoprostane could also be detected in serum 2h after exposure to 200ppm Cl2, which was followed by increased levels of IL-6 and CXCL1/KC and signs of increased fibrinogen and PAI-1. Melphalan, a non-oxidizing mustard gas analog, did not increase the 8-isoprostane levels, indicating that 8-isoprostane is induced in airways through direct oxidation by Cl2. We conclude that 8-isoprostane represents an early biomarker for oxidative stress in airways and in the blood circulation following Cl2-exposure.

The decontamination efficacy of four commercially available skin decontamination products following exposure to the nerve agent VX was evaluated in vitro utilizing a diffusion cell and dermatomed human skin. The products included were Reactive Skin Decontamination Lotion (RSDL), the Swedish decontamination powder 104 (PS104), the absorbent Fuller's Earth and the aqueous solution alldecontMED. In addition, various decontamination procedures were assessed to further investigate important mechanisms involved in the specific products, e.g. decontamination removal from skin, physical removal by sponge swabbing and activation of degradation mechanisms. The efficacy of each decontamination product was evaluated 5 or 30 min after dermal application of VX (neat or diluted to 20% in water). The RSDL-lotion was superior in reducing the penetration of VX through human skin, both when exposed as neat agent and when diluted to 20% in water. Swabbing with the RSDL-sponge during 2 min revealed decreased efficacy compared to applying the RSDL-lotion directly on the skin for 30 min. Decontamination with Fuller's Earth and alldecontMED significantly reduced the penetration of neat concentration of VX through human skin. PS104-powder was insufficient for decontamination of VX at both time-points, independently of the skin contact time of PS104. The PS104-slurry (a mixture of PS104-powder and water), slightly improved the decontamination efficacy. Comparing the time-points for initiated decontamination revealed less penetrated VX for RSDL and Fuller's Earth when decontamination was initiated after 5 min compared to 30 min post-exposure, while alldecontMED displayed similar efficacy at both time-points. Decontamination by washing with water only resulted in a significant reduction of penetrated VX when washing was performed 5 min after exposure, but not when decontamination was delayed to 30 min post-exposure of neat VX. In conclusion, early initiated decontamination with the RSDL-lotion, containing both absorption and degrading properties, allowed to act on skin for 30 min was superior in preventing VX from penetrating human skin. Adding water during decontamination resulted in increased penetration of neat VX, however, water in the decontaminant removal process did not influence the decontamination efficacy. From our study on commercially available decontaminants, it is recommended that future product developments should include both strong absorbents and efficient nerve agent degrading components.

Rapid decline in lung function in COPD is associated with decreased CD25brightFoxP3 regulatory T cells in BAL

Nerve agents are highly toxic organophosphorus compounds that inhibit acetylcholinesterase resulting in rapid accumulation of the neurotransmitter acetylcholine (ACh) causing a cholinergic syndrome including respiratory failure. In the present study, respiratory responses and antimuscarinic treatment efficacy was evaluated ex vivo using rat precision-cut lung slices (PCLS) exposed to the nerve agent VX. The respiratory effects were evaluated either by adding exogenous ACh directly to the culture medium or by applying electric-field stimulation (EFS) to the PCLS to achieve a release of endogenous ACh from neurons in the lung tissue. The airway contraction induced by both methods was enhanced by VX and resulted in lingering airway recovery, in particular when airways were exposed to a high VX-dose. Both contractions induced by EFS and exogenously added ACh were significantly reduced by administration of the antimuscarinic drugs atropine or scopolamine. Two additions of atropine or scopolamine after maximal ACh-induced airway response was demonstrated effective to reverse the contraction. By adding consecutive doubled doses of antimuscarinics, high efficiency to reduce the cholinergic airway response was observed. However, the airways were not completely recovered by atropine or scopolamine, indicating that non-muscarinic mechanisms were involved in the smooth muscle contractions. In conclusion, it was demonstrated that antimuscarinic treatment reversed airway contraction induced by VX but supplemental pharmacological interventions are needed to fully recover the airways. Further studies should therefore clarify the mechanisms of physiological responses in lung tissue following nerve agent exposures to improve the medical management of poisoned individuals.

Inhalation of high concentrations of sulfur dioxide (SO2) affects the lungs and can be immediately dangerous to life. We examined the development of acute and long-term effects after exposure of SO ...

Unintentional exposure to potent synthetic opioids during law enforcement seizures and rescue operations can potentially result in incapacitating effects or life-threatening respiratory depression. The hazard comes mainly from inhalation exposure, however, the skin contact risk should be considered. In the present study, the skin penetration of fentanyl and the efficacy of different decontamination protocols were evaluated by applying two forms of fentanyl on dermatomed human skin mounted in a diffusion cell. Studies were performed on dry skin or skin moistened by water, sweat or hand sanitizer. The free base of fentanyl displayed greater skin penetration ability than the hydrochloride salt and a higher steady state penetration rate of fentanyl in solution compared to powder on dry skin. Sweaty skin increased the penetration rate, both when applied in solution and as powder. The hand sanitizer increased skin penetration of the free base fentanyl but not the hydrochloride salt. Of the evaluated decontamination procedures, only soapy water demonstrated a general efficacy. In conclusion, the skin contact hazard of fentanyl is highly dependent on the exposure conditions and contamination density. The risk for physiological effects of fentanyl is assessed to occur only at very high exposures on sweaty skin. In such events, skin decontamination using soap and water is estimated to be a sufficient decontamination procedure.

There is a compelling need to understand and assess the toxicity of industrially produced nanoparticles (NPs). In order to appreciate the long-term effects of NPs, sensitive human-based screening tests that comprehensively map the NP properties are needed to detect possible toxic mechanisms. Animal models can only be used in a limited number of test applications and are subject to ethical concerns, and the interpretation of experiments in animals is also distorted by the species differences. Here, we present a novel easy-to-perform highly sensitive whole-blood model using fresh non-anticoagulated human blood, which most justly reflects complex biological cross talks in a human system. As a demonstrator of the tests versatility, we evaluated the toxicity of TiO2 NPs that are widely used in various applications and otherwise considered to have relatively low toxic properties. We show that TiO2 NPs at very low concentrations (50 ng/mL) induce strong activation of the contact system, which in this model elicits thromboinflammation. These data are in line with the finding of components of the contact system in the protein corona of the TiO2 NPs after exposure to blood. The contact system activation may lead to both thrombotic reactions and generation of bradykinin, thereby representing fuel for chronic inflammation in vivo and potentially long-term risk of autoimmunity, arteriosclerosis and cancer. These results support the notion that this novel whole-blood model represents an important contribution to testing of NP toxicity.

Chlorine (Cl2) causes tissue damage and a neutrophilic inflammatory response in the airways manifested by pronounced airway hyperreactivity (AHR). The importance of early anti-inflammatory treatment has previously been addressed. In the previous study, both high-dose and low-dose of dexamethasone (DEX) decreased the risk of developing delayed effects, such as persistent lung injuries, while only high-dose treatment could significantly counteract acute-phase effects. One aim of this study was to evaluate whether a low-dose of DEX in combination with the antioxidant N-acetyl cysteine (NAC) and if different treatments (Triptolide, Reparixin and Rolipram) administered 1h after Cl2-exposure could improve protection against acute lung injury in Cl2-exposed mice. BALB/c mice were exposed to 300 ppm Cl2 during 15 min. Assessment of AHR and inflammatory cells in bronchoalveolar lavage was analyzed 24h post exposure. Neither of DEX nor NAC reduced the AHR and displayed only minor effects on inflammatory cell influx when given as separate treatments. When given in combination, a protective effect on AHR and a significant reduction in inflammatory cells (neutrophils) was observed. Neither of triptolide, Reparixin nor Rolipram had an effect on AHR but Triptolide had major effect on the inflammatory cell influx. Treatments did not reduce the concentration of either fibrinogen or plasminogen activator inhibitor-1 in serum, thereby supporting the theory that the inflammatory response is not solely limited to the lung. These results provide a foundation for future studies aimed at identifying new concepts for treatment of chemical-induced lung injury. Studies addressing combination of anti-inflammatory and antioxidant treatment are highly motivated.

Iron-oxide nanoparticles (NPs) generated by environmental events are likely to represent health problems. α-Fe

Inhalation of sulfur dioxide (SO 2 ) primarily affects the lungs and exposure to high concentrations can be immediately dangerous to life. The response after inhalation of SO 2 implicates that the early response involves tissue injury, neutrophilic lung inflammation and airway hyperresponsiveness (AHR). In rats, lung fibrosis is evident 14 days post exposure and early treatment with a single dose of Dexamethasone (DEX) significantly down-modulates the acute inflammatory response in airways. However, this treatment is not sufficient for complete protection against the pulmonary toxicity. The aim was to evaluate whether repeated treatment with DEX alone or in combination with the antioxidant N-acetyl-L-cysteine(NAC) and the anti-fibrotic substance, Pirfenidone (PFD), administered 1h, 5h and 23h after SO 2 -exposure (2200ppm, 10min) could counteract the inflammatory responses, AHR and lung fibrosis in Sprague-Dawley rats. All treatment approaches significantly reduced the total leukocyte response but only combined DEX and NAC reduced the number of neutrophils in BAL. PFD reduced methacholine-induced AHR to almost control levels, in contrast to DEX and DEX/NAC which only provided partial protection against AHR. Only DEX treatment reduced the collagen formation in lung tissue. In conclusion, all treatment protocols reduced the acute SO 2 -induced inflammatory response in airways with DEX/NAC treatment slightly more efficient than the other protocols. PFD appeared to be more efficient than DEX and DEX/NAC combination in reduction of AHR. Only DEX treatment was efficient in the reduction of long-term effects monitored 14 days post exposure. In the future, studies addressing both anti-inflammatory and anti-fibrotic treatment is higly motivated.

In this study, we analyse and discuss the possible impacts on the Swedish society of a volcanic eruption on Iceland, emitting ash particles and large quantities of sulphur dioxide. A scenario was developed, based on the historical Laki eruption of 1783-1784, to describe the content of a potential sulphur fog over time in Sweden. Due to its high complexity and the many uncertainties in the underpinning scientific data, the scenario was developed using a cross-disciplinary approach incorporating experts from different scientific fields. An analysis of the impacts of the hazard on human health, environment and technical equipment was then performed and, finally, representatives from national authorities assessed the overall societal challenges in responding to the consequences of a massive volcanic eruption. The analysis shows that it is the peak concentrations of sulphur dioxide and sulphuric acid rather than the longer periods of moderate concentrations that contribute most to the negative consequences for human health and environment. Altogether, three societal challenges were identified: the ability to compile and disseminate relevant information fast enough, to perform continuous measurements of concentrations of different substances in affected areas and to meet the large demand for medical care.

Dermal exposure to low volatile organophosphorus compounds (OPC) may lead to penetration through the skin and uptake in the blood circulation. Skin decontamination of toxic OPCs, such as pesticides and chemical warfare nerve agents, might therefore be crucial for mitigating the systemic toxicity following dermal exposure. Reactive skin decontamination lotion (RSDL) has been shown to reduce toxic effects in animals dermally exposed to the nerve agent VX. In the present study, an in vitro flow-through diffusion cell was utilized to evaluate the efficacy of RSDL for decontamination of VX exposed to human epidermis. In particular, the impact of timing in the initiation of decontamination and agent dilution in water was studied. The impact of the lipophilic properties of VX in the RSDL decontamination was additionally addressed by comparing chemical degradation in RSDL and decontamination efficacy between the VX and the hydrophilic OPC triethyl phosphonoacetate (TEPA). The epidermal membrane was exposed to 20, 75 or 90% OPC diluted in deionized water and the decontamination was initiated 5, 10, 30, 60 or 120min post-exposure. Early decontamination of VX with RSDL, initiated 5-10min after skin exposure, was very effective. Delayed decontamination initiated 30-60min post-exposure was less effective but still the amount of penetrated agent was significantly reduced, while further delayed start of decontamination to 120min resulted in very low efficacy. Comparing RSDL decontamination of VX with that of TEPA showed that the decontamination efficacy at high agent concentrations was higher for VX. The degradation mechanism of VX and TEPA during decontamination was dissected by

We investigated acute and delayed respiratory changes after inhalation exposure to chlorine (Cl2) with the aim to understand the pathogenesis of the long-term sequelae of Cl2-induced lung-injury. In a rat model of nose-only exposure we analyzed changes in airway hyperresponsiveness (AHR), inflammatory responses in airways, expression of pro-inflammatory markers and development of lung fibrosis during a time-course from 5h up to 90days after a single inhalation of Cl2. A single dose of dexamethasone (10mg/kg) was administered 1h following Cl2-exposure. A 15-min inhalation of 200ppm Cl2 was non-lethal in Sprague-Dawley rats. At 24h post exposure, Cl2-exposed rats displayed elevated numbers of leukocytes with an increase of neutrophils and eosinophils in bronchoalveolar lavage (BAL) and edema was shown both in lung tissue and the heart. At 24h, the inflammasome-associated cytokines IL-1β and IL-18 were detected in BAL. Concomitant with the acute inflammation a significant AHR was detected. At the later time-points, a delayed inflammatory response was observed together with signs of lung fibrosis as indicated by increased pulmonary macrophages, elevated TGF-β expression in BAL and collagen deposition around airways. Dexamethasone reduced the numbers of neutrophils in BAL at 24h but did not influence the AHR. Inhalation of Cl2 in rats leads to acute respiratory and cardiac changes as well as pulmonary inflammation involving induction of TGF-β1. The acute inflammatory response was followed by sustained macrophage response and lack of tissue repair. It was also found that pathways apart from the acute inflammatory response contribute to the Cl2-induced respiratory dysfunction.

A flow-through diffusion cell was validated for in vitro human epidermal penetration studies of organophosphorus compounds (OPCs) applied by infinite dosing. By testing OPCs with similar molecular weight but different physicochemical properties, it was shown that hydrophilic and lipophilic properties are major determinants for the penetration rate. Lipophilic OPCs displayed maximum cumulative penetration in the 20-75% agent concentration range whereas the hydrophilic OPCs displayed maximum cumulative penetration at 10 or 20% agent concentration. Low penetration was observed for all agents at 1% agent concentration or when applied as neat agents. The impact of the receptor solution composition was evaluated by comparing the penetration using receptor solutions of different ratios of ethanol and water. For diluted OPCs, a high concentration of ethanol in the receptor solution significantly increased the penetration compared to lower concentrations. When OPCs were applied as neat agents, the composition of the receptor solution only affected the penetration for one of four tested compounds. In conclusion, the flow-through diffusion cell was useful for examining the penetration of OPCs through the epidermal membrane. It was also demonstrated that the penetration rates of OPCs are strongly influenced by dilution in water and the receptor fluid composition.

The aim of this study was to investigate the inflammatory and immunological responses in airways and lung-draining lymph nodes (LDLNs), following lung exposure to iron oxide (hematite) nanoparticles (NPs). The responses to the hematite NPs were evaluated in both healthy non-sensitized mice, and in sensitized mice with an established allergic airway disease. The mice were exposed intratracheally to either hematite NPs or to vehicle (PBS) and the cellular responses were evaluated on days 1, 2, and 7, post-exposure. Exposure to hematite NPs increased the numbers of neutrophils, eosinophils, and lymphocytes in the airways of non-sensitized mice on days 1 and 2 post-exposure; at these time points the number of lymphocytes was also elevated in the LDLNs. In contrast, exposing sensitized mice to hematite NPs induced a rapid and unspecific cellular reduction in the alveolar space on day 1 post-exposure; a similar decrease of lymphocytes was also observed in the LDLN. The results indicate that cells in the airways and in the LDLN of individuals with established airway inflammation undergo cell death when exposed to hematite NPs. A possible explanation for this toxic response is the extensive generation of reactive oxygen species (ROS) in the pro-oxidative environment of inflamed airways. This study demonstrates how sensitized and non-sensitized mice respond differently to hematite NP exposure, and it highlights the importance of including individuals with respiratory disorders when evaluating health effects of inhaled nanomaterials.