Low molecular weight chemical-induced occupational asthma : The focus on alveolar macrophages

Abstract

Asthma is a very common disorder and its prevalence has increased over the past two to three decades. The proportion of cases attributable to occupational exposure at the workplace is estimated at ~10% of adult-onset asthma. Most cases of occupational asthma are caused by low molecular weight (LMW) compounds. These compounds are too small to be immunogenic by themselves and need to bind to endogenous proteins upon entrance of the body to do so. Relatively little is known about the role of the alveolar macrophage (AM) in LMW compound-induced occupational asthma. This is rather surprising, since AMs are one of the first cells to encounter these LMW compounds upon inhalation due to their location at the interface between air and lung tissue. Furthermore these cells have the capacity to release both pro- and anti-inflammatory mediators during airway inflammation. For that reason, it was tried in this thesis to unravel some of the functions of AMs in LMW compound-induced occupational asthma. Depletion of AMs using clodronate -containing liposomes is a valid approach to study the role of AMs in asthma. In this thesis it was observed that liposomes with a negatively charged bilayer made under aseptic conditions with pyrogen -free components are the most efficient in depleting AMs without attracting inflammatory cells into the airways. Therefore, this depletion method was used to study the role of AMs an animal model for trimellitic anhydride (TMA)-induced occupational asthma using the BN rat. Occupational asthma was induced in these rats by skin sensitization and AMs were depleted 1 day prior to airway inhalation challenge. Since it is speculated that TMA needs to bind to endogenous proteins to become immunogenic, rats were challenged with either TMA or TMA coupled to bovine serum albumin (BSA). The results presented in this thesis show that the role of AMs in a model for TMA-induced occupational asthma is not straightforward. These cells intensify the early asthmatic response, but only in reaction to TMA and not TMA-BSA. Their role in allergic airway inflammation, as measured 24 h after inhalation challenge, is mainly immunologically non-specific. Due to their capacity to reduce irritant properties of TMA and TMA-BSA they probably have an important function in the clearance of these compounds from the airways.