Dexamethasone impairs pulmonary defence againstPseudomonas aeruginosathrough suppressing iNOS gene expression and peroxynitrite production in mice

Abstract

SUMMARYTo elucidate the in vivo mechanisms involved in the impairment in pulmonary defence as the result of treatment with glucocorticoids, we established fatal pneumonia with bacteraemia in dexamethasone (DEX)-treated mice by means of an intratracheal challenge of Pseudomonas aeruginosa. An increased neutrophil influx was observed in bronchoalveolar lavage (BAL) fluids from both untreated and DEXtreated mice. The complete suppression of an inducible isoform of nitric oxide synthase (iNOS) mRNA expression and tumour necrosis factor alpha (TNF-a ) production during the early phase of pneumonia, but not CXC chemokine production, were found in the case of the DEX-treated mice. An immunohistochemical study with a specific antibody also revealed negative staining for nitrotyrosine in the lung tissue of DEX-treated mice, while the formation of nitrotyrosine, which indirectly indicates the generation of peroxynitrite with a potent bactericidal activity, was detected clearly in the bronchial epithelium as well as alveolar phagocytic cells of lung tissue from untreated mice. Furthermore, an intraperitoneal administration of S-methyl-isothiourea (SMT), a potent inhibitor of NOS, significantly decreased the survival and increased bacterial density in the case of untreated mice. In contrast, no significant effects on the survival and bacterial density in the lung and blood were found as the result of treatment with SMT in DEX-treated mice. Collectively, a complete repression of iNOS gene expression and a lack of the generation of peroxynitrite as well as an inhibition of TNF-a production in the lung appeared to be responsible for the progression of the fatal pneumonia due to P. aeruginosa in DEX-treated mice.

Pseudomonas aeruginosaActivates Human Mast Cells to Induce Neutrophil Transendothelial Migration Via Mast Cell-Derived IL-1α and β

“…To determine whether P. aeruginosa-induced MC IL-1␣ and IL-1␤ can be regulated, dexamethasone and IL-10 were chosen because corticosteroids and IL-10 have been directly or indirectly implicated in P. aeruginosa infection (42)(43)(44)(45)(46). We demonstrated that dexamethasone markedly inhibited P. aeruginosa-induced IL-1␣, IL-1␤, as well as TNF-␣ production by human MC.…”

“…Indeed, corticosteroids have demonstrated a beneficial effect on pulmonary function in CF patients with chronic P. aeruginosa infection (46). However, the multiple targets other than MC of IL-10 and dexamethasone may not always be beneficial should the IL-10 or dexamethasone overly suppress normal host defenses (42,44). The adverse effects of corticosteroids due to their nonspecific immunosuppressive actions limit their application in CF patients (50).…”

Ohr plays a central role in bacterial responses against fatty acid hydroperoxides and peroxynitrite

“…Therefore, it is feasible that Ohr plays a relevant role in vivo in the reduction of peroxynitrite. This role might be significant, especially considering that inducible nitric oxide synthase (and possibly peroxynitrite as a product of nitric oxide) displays a crucial role in the pulmonary response to P. aeruginosa infection (42,56). Also for plant pathogens (e.g., X. fastidiosa), peroxynitrite and other nitric oxide-mediated processes are emerging as relevant players in defense responses (41).…”

Modulatory Effects of Dexamethasone upon Virulence Attributes of Pseudomonas Aeruginosa ATCC® 27853™

“…Aliquots of 100 μL of 24 h old dexamethasone-adapted cells containing ca. 1×10 8 CFU mLG 1 were transferred to wells and the plates were incubated for 2 h, at 37°C and 150 rpm. The wells were drained by aspiration and gently washed once with sterile water.…”

“…This molecule is used as anti-inflammatory and anti-allergic drug, usually prescribed on the treatment of cystic fibrosis. However, available data about the interplay between dexamethasone and P. aeruginosa infection shows that high doses of glucocorticoid may impair pulmonary host defense by increasing bacterial density 8 . By other side, it is practically impossible to avoid the exposition of a pathogen as P. aeruginosa after the xenobiotic intake 9 .…”