Prostaglandin modulation of airway hyperresponsiveness and inflammation in murine models of asthma
Allergic asthma is an inflammatory disease of the airways and is characterised by chronic inflammation, reversible bronchoconstriction and airway hyperresponsiveness (AHR). The cyclooxygenases (COXs) are key enzymes in the biosynthesis of prostaglandins, which have diverse physiological and pathological functions, and are also important modulators of inflammatory responses in the lung. However, the role of COX-derived prostanoids in AHR and airway inflammation is still not fully understood. The overall aim of this Thesis was to define the role of COX-derived products in allergic airway responses in experimental mouse models of asthma.
In the present work, lung physiology was measured using the flexiVent® system for direct measurements of respiratory system mechanics. Inflammation was assessed by measuring numbers of inflammatory cells in bronchoalveolar lavage (BAL) fluid as well as levels of inflammatory mediators in BAL fluid and lung tissue. Histological analysis of the lung tissue was also performed to assess possible structural changes. The aim of the first part of this Thesis was to develop an improved protocol for experimental studies of AHR and airway inflammation in sensitised and challenged mice, in order to optimise the delivery route and doses of allergen for antigen challenge. The result established that intranasal challenge of BALB/c mice caused a dose-dependent increase in AHR, whereas the BAL fluid cell response was augmented to the same extent by all doses of allergen. Intranasal challenge causes a more pronounced induction of both AHR and inflammation in sensitised BALB/c mice, compared to aerosol delivery of the same antigen.
The second part of this Thesis aimed to define the function of the prostaglandins in the mouse models of allergic airway inflammation. The role of the prostaglandins was investigated both by using intervention with non-steroidal anti-inflammatory drugs (NSAIDs), as well as genetically modified mice where the synthesis of prostaglandin (PG) E2 had been disrupted by removal of one of the prostaglandin E synthases (mPGES-1). The findings support the concept that in general, COX products have a bronchoprotective function in the airways, i.e. local release of PGE2 modulates the airway smooth muscle reactivity and protects against excessive airway narrowing. Furthermore, the bronchoprotective effects in allergic airway inflammation are mainly due to PGE2, primarily generated by mPGES-1. The two isoenzymes, COX-1 and COX-2, also appeared to have separate functions, whereby COX-1 predominantly generated the prostaglandins recovered in BAL fluid and COX-2 activity was associated with the accumulation of inflammatory cells in BAL fluid. It is not clear, which prostaglandin mediated the COX-2 dependent effects on cellular inflammation. However, the observations suggest that neither mPGES-1 nor PGE2 are involved in the inhibitory function of COX-2 on cell recruitment in the allergic airway reaction.
Taken together, the present Thesis supports the concept that AHR and the inflammatory response are distinct, and at least in part, uncoupled events. Furthermore, the findings raise awareness that BAL fluid inflammation is not a predictive surrogate marker of AHR. Finally, inhibition of PGE2 has been suggested as a target for anti-inflammatory therapies in humans, as PGE2 is a pro-inflammatory mediator and is involved in many inflammatory diseases. However, it is possible that inhibition of mPGES-1-derived PGE2 may have negative consequences in the airways.
List of scientific papers
I. Swedin L, Ellis R, Kemi C, Ryrfeldt Å, Inman M, Dahlén SE, Adner M (2010). "Comparison of aerosol and intranasal challenge in a mouse model of allergic airway inflammation and hyperresponsiveness." International Archives of Allergy and Immunology. 153(3): 249-58.
https://pubmed.ncbi.nlm.nih.gov/20484923
II. Swedin L, Neimert-Andersson T, Hjoberg J, Jonasson S, van Hage M, Adner M, Ryrfeldt A, Dahlén SE (2009). "Dissociation of airway inflammation and hyperresponsiveness by cyclooxygenase inhibition in allergen challenged mice." Eur Respir J. 34(1): 200-8.
https://pubmed.ncbi.nlm.nih.gov/19251789
III. Swedin L, Ellis R, Neimert-Andersson T, Ryrfeldt A, Nilsson G, Inman M, Dahlén SE, Adner M (2010). "Prostaglandin modulation of airway inflammation and hyperresponsiveness in mice sensitized without adjuvant." Prostaglandins Other Lipid Mediat. 92(1-4): 44-53.
https://pubmed.ncbi.nlm.nih.gov/20214998
IV. Swedin L, Kemi C, Lundström S, Lindgren S, Wheelock C, Ryrfeldt Å, Adner M, Dahlén SE (2010). "Deletion of microsomal PGE synthase-1 enhances airway hyperresponsiveness in a mouse model of chronic airway inflammation." [Manuscript]
History
Defence date
2010-06-11Department
- Institute of Environmental Medicine
Publication year
2010Thesis type
- Doctoral thesis
ISBN
978-91-7409-924-9Number of supporting papers
4Language
- eng