Induction of a non-allergic inflammation in the human respiratory tract by organic dust

• Swine farming is an occupation associated with high exposure levels to organic dust, but gases such as ammonia and hydrogen sulphide are also contributing to the potentially hazardous exposure. The prevalences for respiratory symptoms, chronic or work-related, are increased among swine farmers, compared to both the normal population as well as other farming categories. Healthy subjects, previously unexposed to farming environment, developed an intense airway inflammation following three hours of exposure during weighing pigs or during cleaning procedure of an evacuated stable using a high-pressure cleaner. The inflammation was characterised by an increased bronchial responsiveness to methacholine between approximately 1 to 3 dose-doubling steps as well as an extensive migration of inflammatory cells, predominantly neutrophils, into the upper and lower airways. Elevated levels of the chemotactic factor IL-8 found in lavage fluid from the airways most likely achieve this accumulation of neutrophils. The significant correlation between changes in IL-8 levels and increased concentrations of neutrophils found in nasal lavage fluid supports such a theory. Other chemoattractants, could however, also contribute to the recruitment of neutrophils, since increased levels of LTB4 were demonstrated in the upper airways. Other signs of an induced inflammatory reaction were increased post-exposure levels of the inflammatory cytokine IL-6 in nasal lavage fluid and peripheral blood. Involvement of cysteinyl-leukotrienes (cys-LTs) was also established. A local production of LTE4 was detected in the upper airways following exposure as well as an increased whole body formation of cys-LTs measured as increased levels of urinary LTE4. The cys-LTs were hypothesised to be contributing factors to the increased bronchial responsiveness. The intervention study with an inhibitor of leukotriene biosynthesis could not clarify this assumption due to an insufficient inhibitory effect on urinary LTE4 excretion. Signs of mast cell activation were also demonstrated by increased levels of PGD2 , a mast cell mediator, measured as increased urinary levels of the PGD2 metabolite 9a, 11b-PGF2. No relationship between measured inflammatory mediators and increased bronchial responsiveness could be detected, indicating that the airway response was not caused directly by mediator release. Instead, swelling of the airway mucosa and increased secretions due to the general inflammatory reaction could lead to an airway narrowing that would enhance the post-exposure response to methacholine. Endotoxin has been postulated as the main factor behind respiratory illness in the farming environment. This hypothesis is not supported by our studies. Other agents, originating from Gram-positive bacteria are probably important contributors to the induction of the inflammatory reaction after swine house exposure. The perhaps most intriguing finding regarding exposure in this thesis, was the discovery that even if the healthy volunteers were equipped with a half mask with a particle filter during the exposure, they still responded with an increased bronchial responsiveness, although somewhat attenuated. However, the respiratory device showed better effect regarding reactions in the upper airways. This implicates a role for gases (e.g. ammonia) in the development of increased bronchial responsiveness in healthy, previously unexposed, subjects following an acute exposure in the swine farm environment. On the other hand, the particles seem to have a more prominent role for the reactions in the upper airways.

Nyckelord

Swine farmers, airway inflammation, bronchial responsiveness, organic dust, interleukins, lekotrienes

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