Modulation by Sex Hormones of Inflammation and Susceptibility to Pseudomonas Aeruginosa in Cystic Fibrosis Airways

Modulation by Sex Hormones of Inflammation and Susceptibility to Pseudomonas Aeruginosa in Cystic Fibrosis Airways - A Pilot Study

The general objective is to elucidate the mechanisms whereby sex hormones may modulate the severity of respiratory disease. An important component of this proposal is a systematic and intensive approach to characterize how the cellular and cytokine components of airway inflammation respond to fluctuations in sex hormone levels.

The effects of menstrual fluctuations in levels of sex hormones on inflammation and bacterial load in respiratory secretions of CF patients will also be determined.

Most CF patients die because of chronic lung infection with P. aeruginosa, chronic inflammation and progressive airway damage. Agents that reduce inflammation or enhance airway antibacterial defences hold potential therapeutic value. Therefore, there is considerable current interest in identifying and stimulating the activities of these agents. Although sex hormones are generally acknowledged to modulate respiratory inflammation, the downstream mechanism of such action remains incompletely understood.

We have identified three antimicrobial peptides (AMPs), responsive to sex hormone in the CF human respiratory tract, including one (LTF) with known activity against P. aeruginosa biofilm formation. Our preliminary results show additive activity of LTF and STH against P. aeruginosa biofilm formation, and that LTF and STH also inhibit attachment of P. aeruginosa to airway epithelial cells. Taken together, these findings are consistent with the concept that female sex hormones exert their negative effect on the CF lung, in part, by reducing the levels of these AMPs in the airway. The next step is to determine if female sex hormones alter airway inflammation and infection or AMP levels in the respiratory secretions of CF patients.

Inclusion Criteria:

FEMALES WITH CF

• Sexually mature female CF patients followed at the Toronto CF Clinics of The Hospital for Sick Children (adolescents) or St. Michael's Hospital (adults)
• 14-28 years of age
• Diagnosis of CF is based on a typical clinical picture and confirmed by repeated sweat chloride values > 60 mEq/L as determined by pilocarpine ionophoresis (minimum 100mg sweat)
• Have regular, normal menses
• Able to give consent on her own behalf

FEMALES WITHOUT CF

• Sexually mature females
• 14-28 years of age
• Have regular, normal menses
• Able to give consent on her own behalf

MALES WITH CF

• Sexually mature male CF patients followed at the Toronto CF Clinics of The Hospital for Sick Children (adolescents) or St. Michael's Hospital (adults)
• 14-28 years of age
• Diagnosis of CF is based on a typical clinical picture and confirmed by repeated sweat chloride values > 60 mEq/L as determined by pilocarpine ionophoresis (minimum 100mg sweat)
• Able to give consent on his own behalf

MALES WITHOUT CF

• Sexually mature males
• 14-28 years of age
• Able to give consent on his own behalf

Exclusion Criteria:

• Is a smoker
• Has had an upper respiratory tract infection within the preceding two weeks
• Is taking systemic oral contraceptive therapy
• Is pregnant
• Has used furosemide or amiloride or had a pulmonary exacerbation in the previous month (Acute exacerbations are defined as 3 or more of the following symptoms or signs: increased cough, change in volume, colour or thickness of the sputum, fever, hemoptysis, increased shortness of breath, change in their chest radiograph or a fall in pulmonary function (FEV1) of >10% from baseline)
• Unable to give consent on his/her own behalf