Increased expression of inducible nitric oxide synthase and cyclo-oxygenase-2 in the airway epithelium of asthmatic subjects and regulation by corticosteroid treatment

A E Redington, Q H Meng, D R Springall, T J Evans, C Créminon, J Maclouf, S T Holgate, P H Howarth, J M Polak, A E Redington, Q H Meng, D R Springall, T J Evans, C Créminon, J Maclouf, S T Holgate, P H Howarth, J M Polak

Abstract

Background: Nitric oxide (NO) and prostanoids are mediators of vascular and bronchial tone that are postulated to be involved in asthma. Increased levels of both are found in asthmatic subjects and are synthesised by enzymes that have cytokine inducible forms: inducible NO synthase (iNOS) and cyclo-oxygenase-2 (COX-2), respectively. We hypothesised that the in vivo expression of iNOS and COX-2 in the airways would be increased in asthma, and that these cytokine inducible enzymes may represent targets for regulation by corticosteroid treatment.

Methods: Bronchial biopsy specimens were obtained from three groups of subjects: atopic asthmatics treated with beta(2) agonists alone (n=7), atopic asthmatics additionally receiving regular treatment with corticosteroids (n=8), and non-asthmatic control subjects (n=10). Expression of iNOS and COX-2 mRNA and immunoreactive protein was studied using in situ hybridisation and quantitative immunohistochemistry.

Results: Immunoreactivity and the hybridisation signal for iNOS and COX-2 were mainly localised in the airway epithelium. The proportion of epithelium immunostained was significantly greater in the non-steroid treated asthmatic subjects (iNOS 8.6 (1.8)%; COX-2 26.3 (4.6)%) than either the steroid treated asthmatics (iNOS 3.4 (1.0)%, p=0.009; COX-2 13.0 (0.6)%, p=0.0015) or the non-asthmatic controls (iNOS 4.2 (0.9)%, p=0.018; COX-2 11.6 (0.6)%, p=0.0003). Similarly, the hybridisation signal was stronger in the non-steroid treated group of asthmatic subjects than in the other two groups.

Conclusions: These findings highlight the potential role of the airway epithelium both as a contributor to the inflammatory process in asthma and as a target for inhaled corticosteroid treatment in this disease.

References

    1. Am J Respir Crit Care Med. 1997 May;155(5):1763-9
    1. Am J Respir Crit Care Med. 1997 Feb;155(2):670-5
    1. J Allergy Clin Immunol. 1997 Oct;100(4):544-52
    1. Thorax. 1997 Nov;52(11):940-5
    1. Clin Exp Allergy. 1998 Sep;28(9):1050-8
    1. Eur Respir J. 1999 May;13(5):999-1007
    1. Eur Respir J. 1997 May;10(5):1026-32
    1. Am J Respir Crit Care Med. 2000 Feb;161(2 Pt 1):636-40
    1. N Engl J Med. 1984 Jul 26;311(4):209-13
    1. Br J Pharmacol. 1989 Mar;96(3):688-92
    1. Am Rev Respir Dis. 1989 Aug;140(2):449-59
    1. Biochem Biophys Res Commun. 1989 Dec 15;165(2):888-94
    1. J Biol Chem. 1990 Jul 5;265(19):10805-8
    1. Am Rev Respir Dis. 1990 Jul;142(1):126-32
    1. Biochem Biophys Res Commun. 1991 Dec 16;181(2):852-7
    1. Proc Natl Acad Sci U S A. 1992 Jun 1;89(11):4888-92
    1. Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7384-8
    1. Histochemistry. 1992 Nov;98(4):259-66
    1. Am Rev Respir Dis. 1993 Mar;147(3):529-34
    1. Biochem Biophys Res Commun. 1993 Mar 15;191(2):503-8
    1. FEBS Lett. 1993 Sep 13;330(2):156-60
    1. Am J Respir Cell Mol Biol. 1993 Oct;9(4):371-7
    1. Biochemistry. 1993 Nov 2;32(43):11600-5
    1. J Biol Chem. 1993 Nov 5;268(31):23448-54
    1. Reg Immunol. 1993 May-Aug;5(3-4):174-200
    1. Br J Pharmacol. 1993 Oct;110(2):739-46
    1. Lancet. 1993 Dec 18-25;342(8886-8887):1510-3
    1. Am Rev Respir Dis. 1993 Dec;148(6 Pt 1):1474-8
    1. Lancet. 1994 Jan 15;343(8890):133-5
    1. Lancet. 1994 Jan 15;343(8890):146-7
    1. Proc Natl Acad Sci U S A. 1994 Jan 4;91(1):267-70
    1. Eur Respir J. 1993 Oct;6(9):1368-70
    1. Biochem Biophys Res Commun. 1994 Aug 30;203(1):209-18
    1. Br J Pharmacol. 1994 Nov;113(3):1008-14
    1. Am J Respir Crit Care Med. 1995 Sep;152(3):892-6
    1. Am J Respir Crit Care Med. 1996 Jan;153(1):128-35
    1. Am J Respir Crit Care Med. 1996 Jan;153(1):454-7
    1. Lancet. 1996 Aug 10;348(9024):374-7
    1. Proc Natl Acad Sci U S A. 1996 Sep 3;93(18):9553-8
    1. Prostaglandins. 1996 Nov;52(5):341-59
    1. Life Sci. 1997;60(1):67-78

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe