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. Author manuscript; available in PMC: 2014 Dec 29.
Published in final edited form as: Clin Exp Allergy. 2008 Jun 28;38(9):1526–1535. doi: 10.1111/j.1365-2222.2008.03038.x

Bakery flour dust exposure causes non-allergic inflammation and enhances allergic airway inflammation in mice

Paolo Marraccini 1, David M Brass 2, John W Hollingsworth 3, Shuichiro Maruoka 2, Stavros Garantziotis 4, David A Schwartz 5
PMCID: PMC4278578  NIHMSID: NIHMS497849  PMID: 18564331

Abstract

Background

Baker’s asthma is one of the most commonly reported occupational lung diseases in countries where fresh bread is baked daily in large quantities, and is characterized by rhinitis, bronchial hyperresponsiveness, and reversible airflow obstruction. Epidemiological studies have identified pre-existing atopy as an important risk factor for developing baker’s asthma, yet the etiology and pathogenesis of baker’s asthma remain poorly understood.

Objective

We sought to develop a mouse model of baker’s asthma that could be used to characterize the development and progression of baker’s asthma.

Methods

We were unable to sensitize mice to bakery flour dust or flour dust extract. We assessed total inflammatory cells, cellular differential, total serum IgE and the pro-inflammatory cytokine response to oropharyngeally instilled bakery flour dust or flour dust extract by itself or in the context of OVA sensitization and challenge.

Results

Both bakery flour dust and flour dust extract consistently elicited a neutrophilic inflammation in a tlr4-independent manner; suggesting that endotoxin is not playing a role in the inflammatory response to flour dust. Moreover, bakery flour dust and dust extract significantly enhance the inflammatory response in OVA sensitized and challenged mice.

Conclusions

Bakery flour dust and flour dust extract are strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation.

Keywords: LPS, endotoxin, toll-like receptor 4, occupational airways disease, baker’s asthma, flour dust, allergic asthma

INTRODUCTION

Baker’s asthma was first described 300 years ago by Bernardino Ramazzini in his pioneering work, De Morbis Artificum Diatriba [1]. Today, baker’s asthma is one of the most frequently reported occupational respiratory diseases in western countries [2], and represents more than 20% of insurance compensations due to occupational asthma in Finland and Canada 3]. Characterized by rhinitis which often accompanies respiratory symptoms such as airflow obstruction and bronchial hyper-responsiveness, baker’s asthma has been shown to develop in work environments in which there is continued exposure to bakery flour dust. Respiratory symptoms in bakery workers are commonly believed to be attributable to wheat flour proteins and supplemental enzymes to improve dough quality [4] and there is data in the literature to suggest that levels of exposure to flour dust correlate with health endpoints such as sensitization and respiratory symptoms [5–7]. Additionally, there are studies that identify pre-existing atopy as an important independent risk factor for the development of baker’s asthma [8]. While it is generally believed that sensitization to components of bakery flour dust contribute to the development of baker’s asthma [9], many bakers with airway symptoms are not sensitized to flour allergens as measured by specific IgE, skin prick test, or inhalation tests [10]. Interestingly normal healthy subjects exposed to bakery flour dust have a significant increase in BAL cellularity over baseline despite having no detectable allergic reaction to flour allergens [11]. These observations taken together suggest that adaptive immunity may not be the only mechanism leading to the development of baker’s asthma.

Bakery flour dust is a complex mixture of proteins and other organic materials including bacterial endotoxin [12]. Bacterial endotoxin, or lipopolysaccharide (LPS), is ubiquitous in the environment [13]; especially so in bioaerosols as seen in grain elevators [14]. LPS by itself can contribute to pulmonary neutrophilic inflammation and decrements in lung function in both humans and rodents [15, 16] and can modify the adaptive immune response found in allergic asthma [17]. Our findings indicate that while flour dust causes non-allergic airway inflammation, this is not primarily driven by LPS contamination. Moreover, we found that flour dust can enhance pre-existing allergen-mediated airway inflammation that may be independent of the effects of LPS contamination of bakery flour.

Materials and Methods

Animals

C57BL/6J and BALB/c male mice (6 – 8 wk) were obtained commercially (Jackson Laboratories, Bar Harbor, ME). Tlr4-deficient animals were generously provided by Dr. Akira (Osaka University) and backcrossed onto C57BL/6J for at least 8 generations. Experimental protocols were reviewed and approved by the Institutional Animal Care and Use Committee at the National Institute of Environmental Health Sciences, and were carried out in accordance with the standards established by the U.S. Animal Welfare Acts.

Sensitization with bakery flour dust or flour dust extract

In our initial attempt to sensitize mice to bakery flour dust or flour dust extract six Balb/C or in separate experiments C57BL/6 mice per group were injected intraperitoneally (i.p.) on day 0 and day 7 with either 10 μg bakery flour dust (European whole grain Type 1 flour product dust; codex R1 lot 18/4; obtained through the National Italian Bakeries Association) or 10 μg flour dust extract (IHRP 82; the generous gift of Drs. Adler Dorli and Daniela Roncarolo of Lofarma SpA Milano, Italy) complexed with 2 mg aluminum hydroxide (Pierce, Rockford, IL). On days 14 and 15, mice received saline alone or 0.1 or 1.0 mg of bakery flour dust, or 0.1 or 1.0 mg of flour dust extract via oropharyngeal aspiration in a total volume of 50 μl endotoxin-free PBS as previously described [18]. These experiments were then repeated. In a subsequent attempt to sensitize mice to bakery flour dust or flour dust extract based on a protocol used to sensitize mice to cockroach antigen, six Balb/C mice per group were injected with 10 μg bakery flour dust or flour dust extract on day 0 emulsified in incomplete Freund’s adjuvant. Mice were then given an initial intranasal (i.n.) administration of either 10 μg bakery flour dust or 10 μg flour dust extract on days 14, 22, and 23. Mice were sacrificed and lavaged on day 24.

Flour dust extract

Lofarma IHRP 82 is a sterile low-endotoxin aqueous extract of commercial bakery flour that is used both diagnostically and clinically in allergy immunotherapy (A.M. Cirla, Milan, pers. comm.). This extract contains all the proteins contained in whole bakery flour dust but lacks the insoluble particulate matter starches and gluten contained in whole flour. Flour dust extract is prepared as follows: briefly, an 8% solution of Italian bakery flour (Farina Molino Fiocchi) is prepared in phosphate buffer saline/0.15M NaCl, ph 7.2 and shaken overnight at 4° C. This solution is lyophilized and stored at −20° C. For our experiments, the flour dust extract was resuspended in endotoxin-free PBS immediately prior to instillation as described.

Flour and extract challenge

Six C57BL/6 mice per group were challenged once with saline, low-endotoxin content bovine serum albumin (< 0.01 ng/mg) (Equitech-Bio Inc. Kerrville TX), at 0.1, 0.5 or 1 mg/mouse, bakery flour dust (described above) at 0.1, 0.5 or 1 mg/mouse or flour dust extract (described above) at 12.5, 50 or 125 μg/mouse. All solutions were prepared in endotoxin-free PBS and delivered in a final volume of 50 μl via oropharyngeal aspiration as previously described [18].

Ova sensitization and challenge

Six C57BL/6 mice per group were sensitized on days 0 and 7 by i.p. injections of 10 μg OVA (Sigma, St. Louis, MO) complexed with aluminum hydroxide (Pierce, Rockford, IL). On day 14, mice received either the amount of LPS found in 1 mg of bakery flour dust as determined by LAL (from E. coli serotype O111:B4; Sigma-Aldrich (St. Louis MO); 1.26 ug/mouse or 3,780 EU/mouse), flour dust, endotoxin-free flour dust or flour extract via oropharyngeal aspiration in a final volume of 50 ul prepared in endotoxin-free PBS. Mice were subsequently exposed daily for 40 minutes on three consecutive days to an aerosol of 1% OVA (Sigma, St. Louis, MO) generated using a Collison nebulizer (BGI Inc; Waltham, MA). Animals were harvested 24 hours after the last aerosol challenge.

Analysis of airway inflammation and cytokines in whole lung lavage

Whole lung lavage and cell differentials were determined as previously described [19]. TNF-α, IL-5, MIP-2, KC and IL-17 ELISAs were performed according to the manufacturer’s instructions (R&D Systems; Minneapolis, MN). Serum IgE levels were determined by ELISA according to the manufacturer’s instructions (Pharmingen, San Diego, CA). Total protein was determined by the Lowry method according to manufacturer’s instructions (Bio-Rad; Hercules, CA).

Endotoxin assay and LPS removal from flour dust

The LPS content of flour was assayed using the chromogenic Limulus amoebocyte lysate assay (QCL-1000, Cambrex Bio Science Inc, Walkersville MD). Bacterial LPS was removed from flour dust using the Endo Trap red kit (Profos AG, Germany). Briefly, a prepacked column was filled twice with 6 ml regeneration buffer (phosphate – buffer pH 7.4, LPS concentration < 0.02 EU/ml) and then drained out completely. Equilibration buffer (phosphate – buffer pH 7.4 with 80 mM NaCl and LPS concentration < 0.02 EU/ml) was also added and drained out. The flour dust suspension was then applied to the column and the eluate collected. The measured LPS in reagents used in this study were as follows: flour 3780 EU/mg, flour-extract 365 EU/mg, and LPS-free flour 9 EU/mg.

Histology

After lavage, the left lung of each animal was inflation fixed with 10% neutral buffered formalin at 20 cm H20, embedded in paraffin and cut in 5 μm sections. Full face sections cut parallel to the apex of the pleural surface were stained with Hematoxylin and Eosin. Histological sections presented in figure 6 are 200X original magnification.

Figure 6.

Figure 6

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Vascular cuffing in Balb/C mice sensitized with OVA and pre-challenged with either saline (A) or high dose flour (B) (as described in Materials and Methods) prior to OVA challenge.

Statistical Analyses

ANOVA was used for multiple comparisons. Specific comparisons were made using the Student’s t-test and presented as mean ± SE. Statistical significance was accepted as p < 0.05.

RESULTS

Bakery flour dust and flour dust extract elicit pulmonary neutrophilic inflammation in a tlr4 independent manner

In our initial experiments we attempted to develop a mouse model of baker’s asthma based on the OVA model. However, we were unable to successfully sensitize either C57BL/6 or Balb/C mice to bakery flour such that subsequent challenge with flour dust elicited an allergic inflammatory response. In one experiment we injected Balb/C mice with either bakery flour dust or flour dust extract complexed with alum according to the standard OVA sensitization protocol. We then challenged with either saline, 0.1 mg or 1 mg of whole bakery flour via oropharyngeal aspiration (Figure 1) The inflammatory response to this attempted sensitization and challenge protocol and to all others (Materials and Methods) was neutrophilic. We show in Figure 1D that in this attempted sensitization protocol there was no increase in total serum IgE as the measurable levels were consistent with sham sensitized sham challenged mice in an OVA protocol (Figure 1D left). Had the sensitization been successful we would have expected total serum IgE to be comparable to that seen in OVA sensitized OVA challenged mice (Figure 1D left). Despite the absence of atopic sensitization, neutrophilic inflammation in response to the challenges was a consistent feature of these initial studies (Figure 1C). To address the mechanism by which neutrophils were recruited to the lung in these exposures, we measured protein levels of the neutrophils chemoattractant cytokines Macrophage Inflammatory Protein (MIP)-2, the arbitrarily named cytokine KC [20] and interleukin (IL) 17 in whole lung lavage fluid. We show in Figures 1E and 1F that both MIP-2 and KC are significantly increased as a result of bakery flour exposure in mice we attempted to sensitize with either bakery flour dust or flour dust extract. Interestingly, there was no IL-17 present in whole lung lavage in this experiment or in any subsequent experiment.

Figure 1.

Figure 1

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Inflammatory response of Balb/C mice injected intraperitoneally with alum and either bakery flour dust (Sensitized with Flour) or flour dust extract (Sensitized with Extract) according to the OVA protocol, and then challenged with either saline or flour as indicated. Total pulmonary inflammatory response (A), macrophages in whole lung lavage (B), neutrophilic inflammatory response (C), total serum IgE (D), MIP-2 and KC in mice injected intraperitoneally with alum and flour before flour challenge (E) and MIP-2 and KC in mice injected intraperitoneally with alum and extract before flour challenge (F). Data presented are mean ± SEM. * p<0.05 vs. saline.

To further define and characterize the inflammatory response to bakery flour dust or flour dust extract, mice were challenged with saline; low, medium, or high concentrations of bakery flour dust; flour extract; or BSA as a negative control (Figure 2). Both bakery flour dust and flour dust extract caused a significant, dose-dependent increase in pulmonary neutrophilic inflammation four hours after exposure (Figure 12B). Both MIP-2 and KC protein were induced by instillation of bakery flour dust or flour dust extract as shown in Figures 2E and 2F. Neither cytokine was induced by instillation of BSA as a negative control. Additionally, both flour and flour dust extract caused a significant increase in the overall number of macrophages present in the lung at the high dose, while bakery flour also caused an increase in macrophages at the medium dose (Figure 2C). The concentration of TNF-α protein in whole lung lavage fluid after bakery flour dust instillation was significantly elevated when compared to control groups. TNF-α protein was also significantly elevated at the high dose of extract when compared to control groups. BSA instilled as a control did not elicit significant pulmonary cellular inflammation or TNF-α protein in whole lung lavage fluid (Figure 2D).

Figure 2.

Figure 2

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Inflammatory response to bakery flour dust, flour dust extract or bovine serum albumin (BSA). Total pulmonary inflammatory response (A), neutrophilic inflammatory response (B), macrophage inflammatory response (C), lavageable TNF-α response (D), lavageable MIP-2 (E) and lavageable KC (F) in response to low, medium or high (as described in Materials and Methods) concentrations of bakery flour dust, flour dust extract or BSA. Data presented are mean ± SEM. * p<0.05 vs. saline.

To address the kinetics of, and to further define the overall inflammatory response to bakery flour dust we exposed C57BL/6 mice to a single instillation of bakery flour and examined the inflammatory response 4 hrs and 24 hrs afterwards (Figure 3). Consistent with our earlier observations, both MIP-2 and KC were significantly induced by bakery flour dust when compared to saline controls both 4 and 24 hrs after instillation. We observed that the absolute number of macrophages in whole lung lavage was increased in both flour and saline instillation groups (Figure 3B). However, only bakery flour caused an increase in the absolute number of lavageable PMNs. This inflammatory response was more pronounced 4 hours after the exposure and both the macrophage and the neutrophilic inflammatory responses were still elevated at 24 hours after instillation (Figure 3B & 3C).

Figure 3.

Figure 3

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Time course of pulmonary inflammatory response to high dose flour exposure (as described in Materials and Methods). Total pulmonary inflammatory response (A), macrophage inflammatory response (B), neutrophilic inflammatory response (C), lymphocytic inflammatory response (D), total lavageable MIP-2 (E) and KC (F) are presented. Data presented are Mean ± SEM. * p<0.05 vs saline.

Because we observed endotoxin contamination in the bakery flour used in these experiments (3780 EU/mg) we asked whether LPS contamination was eliciting the pulmonary inflammatory response. To address this question we challenged mice deficient for tlr4, the primary LPS receptor, with bakery flour dust. We show in figure 3 that the biologic response to flour dust is tlr4-independent as both wild-type and tlr4-deficient mice responded similarly to flour dust instillation. These responses are consistent with previous results in which we show significant increases in total cells, macrophages, neutrophils, TNF-α, MIP-2 and KC when compared with the saline-exposed animals.

Bakery flour dust and flour dust-extract enhance pre-existing allergic inflammation

Epidemiologic data suggest that bakery flour dust exposure can contribute to the severity of atopy and allergic asthma. To determine the role of bakery flour dust exposure in the context of pre-existing allergic sensitization, we sensitized Th2 predisposed Balb/C mice to OVA and subsequently challenged them to OVA after saline, flour dust, flour extract, or LPS-free flour instillation. We observed a significant increase in total cells with pre-exposure to flour or flour-extract (Figure 5A). Mice pre-treated with LPS in the same amounts found in 1 mg of bakery flour dust were not different in total number of inflammatory cells (Fig. 5A) when compared to mice pre-treated with saline. Mice pre-exposed to either flour or LPS-free flour had significantly enhanced macrophage (Fig. 5B) and eosinophilic (Fig 5D) inflammation consequent to OVA challenge. Additionally, there was a trend towards a significant increase in eosinophils with flour-extract pre-exposure. We also show significantly elevated TNF-α (Figure 5E) and IL-5 (Figure 5F) protein in whole lung lavage in mice pre-exposed to LPS, flour, or LPS-free flour but not flour extract. Total serum IgE for all exposures (Figure 5G) was also significantly elevated over sham sensitized sham challenged (Saline/Saline) controls although the flour pre-exposed mice did not have enhanced total serum IgE compared to sensitized mice pre-exposed to saline before ova challenge (Figure 5G, black bar; Saline). Consistent with these observations we show in Figure 6 that vascular cuffing is increased in OVA sensitized and challenged mice challenged with bakery flour dust instillation (Figure 6B) when compared with OVA sensitized and challenged mice instilled with saline alone (Figure 6A).

Figure 5.

Figure 5

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Pulmonary inflammatory response to high dose bakery flour dust, LPS-free bakery flour dust, or flour dust extract (as described in Materials and Methods) in the context of OVA sensitization and challenge. Total pulmonary inflammatory response (A), macrophage inflammatory response (B), neutrophils (C), eosinophilic inflammatory response (D), lavageable TNF-α (E), lavageable interleukin (IL)-5 (F) and total serum IgE (G) are presented. Data presented are Mean ± SEM. * p<0.05 vs saline.

DISCUSSION

A more clear understanding of the biological response to organic dust exposure in the work environment has the potential to be of considerable clinical significance. We show here for the first time, that exposure to flour dust can exacerbate allergen-mediated airway inflammation and can lead to acute airway inflammation mediated by increased MIP-2 and KC, yet independent of sensitization to flour dust and independent of the endotoxin content of the dust.

Previous hypotheses have focused on increased levels of ambient flour dust that may be associated with enhanced sensitization to flour proteins [21, 22]. This is supported by the detection of specific IgE antibodies against wheat in some studies [23, 24], although wheat protein specific IgE is not observed in all cohorts of bakers asthma [25]. Ambient flour dust exposure is exceedingly high in most bakeries, ranging from 1 to 10 mg/m3 of respirable air [8, 26] with frequent peaks of greater than 50 mg/m3 [10]. Importantly however, ambient levels of wheat proteins in the air have not reproducibly been associated with the frequency of atopy and asthma [27]. Thus it is unclear whether patients with baker’s asthma represent a distinct population of individuals sensitized to wheat proteins. To address this question experimentally, we first tested the possibility that bakery flour dust could act as a specific allergic antigen. We attempted to develop a mouse model of baker’s asthma based on previously published allergic sensitization and challenge models (Materials and Methods) with bakery flour dust or flour dust extract. In at least four separate experiments we failed to observe an allergic inflammatory (eosinophilic) response to airway challenge with either bakery flour dust or dust extract consequent to intraperitoneal sensitization. However, we consistently observed enhanced neutrophilic inflammation in response to subsequent challenge with flour dust or dust extract in those experiments. Those observations led us to hypothesize that inhalation of flour dust may contribute directly to airways disease in a non allergen sensitization dependent manner. We reasoned that endotoxin contamination of the bakery flour dust or the dust extract might be causing the observed neutrophilic inflammation and that this might in turn explain the lack of a clear correlation between sensitization to wheat allergens and baker’s asthma.

While we found that commercial bakery flour dust contains high concentrations of bacterial endotoxin, our results show surprisingly, that the pro-inflammatory activity of bakery flour dust is not dependent on the ability of the experimental animals to respond to endotoxin. This is supported by the observation that bakery flour dust containing significant amounts of endotoxin causes acute increases in the presence of MIP-2 and KC and neutrophilic inflammation in the lungs of tlr4 deficient mice. We additionally show that flour dust extract, which contains dramatically reduced amounts of endotoxin compared to whole bakery flour dust, also elicits the same response. Thus the role that allergic sensitization to flour proteins may play in the development of baker’s asthma remains an area of debate.

Because we were unsuccessful in sensitizing mice to flour proteins, we considered the possibility that the acute inflammatory response to flour might exacerbate pre-existing allergic asthma in bakers. To address this possibility experimentally we examined the effects of exposure to bakery flour dust in a murine model of pre-existing allergic sensitization. Exposure to flour dust, endotoxin-free flour dust, or flour dust extract, but not LPS by itself, prior to allergen challenge significantly enhanced allergic inflammation, supporting our hypothesis that bakery flour could enhance existing asthma in atopic/allergic individuals. Our observation that bakery flour dust is more potent than flour dust extract in stimulating an inflammatory response, taken with the lack of a clear correlation between sensitization to wheat allergens and baker’s asthma suggest that it is not only sensitization to wheat antigens in bakery flour that may determine predisposition to baker’s asthma. Other non-protein components of the flour may contribute to development of this disease. Additionally, some patients diagnosed with baker’s asthma may in fact be predisposed to allergic asthma independent of sensitization to wheat allergens and the occupational exposure may reveal this predisposition. An alternative hypothesis is that the inflammatory response observed in both C57BL/6 and Balb/C mice is a mild form of contact dermatitis or the early stages of hypersensitivity pneumonitis. We are not aware of any data that suggests that bakers have an increased incidence of extrinsic allergic alveolitis or hypersensitivity pneumonitis although recent case reports show that yeasts can be associated with this pathology [28, 29]. These hypotheses remain to be tested.

We have shown that flour dust is strongly pro-inflammatory and can cause non-allergic airway inflammation and can enhance allergen-mediated airway inflammation. Our results suggest that neither endotoxin in the flour dust nor allergic sensitization to wheat flour proteins is pathogenically related to the airway inflammatory response in our experimental system. Nevertheless, closer regulation of levels of bakery flour dust exposure could have a substantial impact on preventing of baker’s asthma in the workplace; preventive measures and health surveillance of workers with higher risk, such as atopy or previous respiratory symptoms, are strongly recommended.

Figure 4.

Figure 4

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Inflammatory response of C57BL/6 and TLR4 deficient mice to high dose bakery flour dust (as described in Materials and Methods). Total pulmonary inflammatory response (A), macrophage inflammatory response (B), neutrophil inflammatory response (C), lavageable TNF-α (D), MIP-2 (E) and KC (F) are presented. Data presented are Mean ± SEM. * p<0.05 vs saline.

Acknowledgments

Funding Support: This research was supported, in part, by the Intramural Research Program of the National Heart Lung and Blood Institute, the National Institute of Environmental Health Sciences, and by grants from the National Institute of Environmental Health Sciences (ES11961), the National Heart, Lung, and Blood Institute (HL91335), and the National Institute of Allergy and Infectious Diseases (AI058161).

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