Effect of inhaled formyl-methionyl-leucyl-phenylalanine on airway function.

Abstract

Formyl-methionyl-leucyl-phenylalanine (FMLP), a synthetic, acylated tripeptide analogous to bacterial chemotactic factors, has been shown to cause bronchoconstriction in guinea pig, rabbit, and human airways in vitro. To determine whether FMLP causes bronchoconstriction in man in vivo, a preliminary study was undertaken in which five non-smokers (mean age 35 years, FEV1 94% (SEM 5%) predicted) and five smokers (mean age 34 years, FEV, 93% (6%) predicted) inhaled aerosols of FMLP. None of the subjects showed airway hyperresponsiveness to histamine (the provocative concentrations of histamine causing a fall of > 20% in FEV, (PC20) were over 8 mg/ml). FMLP dissolved in 50% dimethylsulphoxide and 50% saline in concentrations of 0, 0-06, 0-12, 025, 0-5, 1-0, 2-0, and 4-0 mg/ml was administered to the subjects by means of a French-Rosenthal dosimeter, FEV, being recorded after inhalation ofeach concentration. Dose dependent falls in FEV, occurred in five non-smokers (geometric mean 1 76, 95% confidence limits 0-87-3-53 mg/ml) and three smokers (0-23, 0O07-0 78 mg/ml), with two smokers not responding by 20% to the highest concentration of FMLP. On a separate day the FMLP dose-response curves were repeated after nebulisation of 500 ,ug of ipratropium bromide. The PC20 FMLP in the responders more than doubled. In six additional normal subjects a histamine inhalation test was performed before and four and 24 hours after inhalation of FMLP. All subjects remained unresponsive to histamine. These results show that FMLP is a potent bronchoconstrictor in some non-asthmatic individuals in vivo and this may be important in bronchoconstriction related to infection in patients with chronic obstructive lung disease.Bacteria elaborate chemotactic factors for leucocytes.'-3 These factors have been isolated and characterised as small molecular weight peptides."5 In subsequent studies of the structure-activity relations of synthetic chemotactic peptides6 the acylated tripeptide formyl-methionyl-leucyl-phenylalanine (FMLP) was shown to be the most active chemotactic agent.With an ED_, for rabbit neutrophil chemotaxis of 70 pmol/l, FMLP is one of the most potent chemotaxins known. The well defined chemical structure of the ligand has permitted detailed studies of the nature of the receptor that is present on macrophages and

Neutrophil–induced human bronchial hyper responsiveness in vitro—pharmacological modulation

“…The synthetie baeterial chemotaetie factor formyl-methionyl-leucylphenylalanine (FMLP) also aetivates neutrophils [7]. In addition it has been shown to cause bronchoconstriction in vitro [8] and in vivo [9]. Human neutrophils primed with GM-CSF and then stimulated with FMLP produee detectable amounts of the leucocyte chemotactic factor leukotriene B4 [10].…”

The effect of anticholinergic and beta-agonist pretreatment on bronchoconstriction induced by N-formyl-methionyl-leucyl-phenylalanine

“…Immediately thereafter a standard doubling-dose response curve to FMLP was performed. The initial concentration given was 0.12 mg•ml•' as no subject had bronchoconstricted by 20% to this concentration in a previous study [10). The subject took: 5 breaths from functional residual capacity (FRC) to total lung capacity (TLC) of each concentration of FMLP using a de Yilbiss 646 nebulizer and a French-Rosenthal dosimeter.…”

“…Virtually all bacteria [7) produce low molecular weight neutrophil chemotactic factors which are known to be oligopeptides [8). Previous work has shown FMLP to contract human bronchial smooth muscle in vitro [9) and to be a bronchoconstrictor when given by inhalation in man in vivo [10). Although bronchial smooth muscle contraction by FMLP was not inhibited by atropine, vagal reflexes may contribute to the bronchoconstriction in vivo as one of the effects of FMLP is an irritating cough.…”

Rejecting Renvoi for Movable Cultural Property: The Islamic Republic of Iran v. Denyse Berend

“…Finally, even though the claimant argued the conventions had been incorporated into French domestic law, Justice Eady stated, These conventions have been around a long time without being incorporated into the law of France, and [Maître Foussard, the French law expert for the defendant] asked rhetorically why as a matter of judicial policy the hypothetical French court should suppose that the time has become ripe for their implementation in 2007. 32 Justice Eady was understandably reluctant to use renvoi to apply Iranian law in this case. Renvoi had never been used in the context of movables in English law.…”