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Silvia, Ferrazzoni (2008) Risposta delle vie aeree indotta da inquinanti ambientali valutata con metodiche prevalentemente non invasive. [Ph.D. thesis]

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Abstract (english)

Inflammation is the main responsible for bronchial hyperresponsiveness, airflow limitation and mucus hypersecretion in chronic obstructive pulmonary diseases as for example in asthma. This has brought us to extensively investigate into the cells types and mediators responsible for the cascade of events which lead from the initial stimulus to an altered airway function.
In the past the main function of the respiratory epithelium was thought to be an inert barrier. It is, in fact, the interface between the internal milieu and the external environment. The bronchial epithelium actually answers external environment changes by freeing a large number of molecules and mediators which modify the lining fluid pH, transmit signals to the immunitary system cells and draws inflammatory cells into the airway lumen.
The expression of inducible form of nitric oxide synthase (iNOS) in the airway epithelium, responsible for the concentration of nitric oxide exhaled (eNO) detectable in the exhaled air, is greatly upregulated after exposure to pro-inflammatory cytokines and oxidants agents. For this reason iNOS has been implicated in the pathogenesis of airway inflammatory response. Patients with asthma have a marked increase in NO in exhaled air.
The loss of integrity of the bronchial epithelium can be associated with alterations of the secretory properties and of an increase of permeability. The Clara cell protein (CC16) is a small anti-inflammatory and immunosuppressive protein which can take part in the protection of the airway and has been measured out in the liquid for the bronchoalveolar lavage (BAL). Increased levels of CC16 in the serum or in the urine may indicate altered permeability of the epithelium barrier due to lung damage.
Occupational asthma is one of the most common respiratory diseases linked to work, in industrialized countries. Isocyanates are important aetiological agents of occupational asthma: because of their chemical and physical characteristics they have an irritating and sensitizing power. Polymeric resins, which are widely used as paints, foams and elastomers derive from isocyanates polymerization .
The present research has hypothesised that the acute response of the respiratory tract induced by isocyanates in sensitised patients, is characterised by the attraction of inflammatory cells into the airway which can be measured by induced sputum, by a particular profile of mediators freed by the epithelium in the exhaled breath, by lining fluid alterations quantifiable in the exhaled breath condensate (pH) and by a bronchiolar damage on measuring mediators peculiar of the airway, in plasma and urine.
In the first phase of the study the measuring methods for exhaled nitric oxide, exhaled breath pH condensate and CC16 in serum and urine were standardized. Then we selected 15 patients with occupational asthma caused by isocyanates, 24 non sensitised control patients and 3 with occupational rhinitis from isocyanates.
Monitoring of the airway acute response was carried out by comparing patients with occupational asthma with the control ones.
Each patient was experimentally exposed to isocyanates concentrations (TDI,MDI or HDI) below TLV Stel (20ppb) and to placebo on different days, in single blind.
The Respiratory function and exhaled NO concentrations were monitored for seven hours after placebo and isocyanates exposure. In order to determine the pH, the exhaled breath condensate was collected seven hours before and after placebo and isocyanates exposure. Later on, subsequent measurements and collections were carried out at the 24th, 48th hours, 7th and 30th days after exposure to ysocianates.
Sputum was induced by hipertonic salty solution aerosol (3-4%) before and 24 hours after exposure. At the same times and 48 hours after exposure venous blood samples and urine were taken in order to determine the clara cell protein (CC16).
The patients with positive specific challenge test (SIC+), in basic situation, presented an eNO concentration of 67.12 ppb[16](geometric mean [SE]). 30 minutes after the specific challenge test, this figure underwent a significant reduction (45 ppb[13.7]) which kept the same values until the second hour after exposure 53.7ppb [14].
Then the eNo concentration increased and reached the highest figure at the 48th hour (118ppb[25]) after exposure. ON the 7th day after exposure eNo had gone back to the basic value. In the control patients, with a negative specific challenge test (SIC-) no variation in the eNO concentration before and after exposure to isocyanates. As for subjects with rhinitis deriving from isocyanates the eNo concentration had a similar course as the control patients'one.
The SIC+ ones showed a meaningful increase in the eosinophils in the induced sputum 24 hours from exposure to ysocianates compared to the basic values (p=0.01). In control patients instead, a meaningful diminution of the percentage of the eosinophils in the sputum 24 hours after exposure to isocyanates (p=0.041) was observed. Moreover a meaningful difference was also observed between the percentage of eosinphilis in the sputum of 24 hours after exposure to isocyanates in test positive patients compared to the control ones (p= 0.0002). No meaningful difference was observed in the neutrophils percentage after exposure to isocyanates in both groups. Grouping all the patients, the variation in the eNo concentration at the 48th hour compared to the basic value (expressed in logarithm) positively correlated with the eosinophils variation (expressed in logarithm) at the 24th hour compared to the basis (p<0.05, rho=0.496).
The pH measurement in the EBC have highlighted a significant increase of the pH at the 7th hour after exposure to placebo (in the afternoon) compared to the basic figures pre-exposure (in the morning) both in the SIC+ and in the SIC- patients, respectively with a significance of p=0.005 and p=0.0013. The same pattern was observed, in both groups of patients, on the exposure to isocyanates day, although the differences did not statistical significant.
The basal figures of CC16 in the serum and urine in SIC+ patients were considerably higher than in the SIC- ones: p=0.0282 and p=0.0169 respectively.
After 7 and 24 hours from exposure to isocyanates no significant variation was observed both in the SIC+ and SIC- patients.
In this research it has been demonstrated that the asthmatic reaction induced by isocyanates is linked to a significant increase in the eNo concentration which reaches the highest figure at the 48th hour after exposure. This increase is belated as it reveals when the bronchoconstriction has been resolved; it is also 24 hours post poned with respect to the increase of the eosinophils in the sputum, which in previous studies showed increase between the 8th and the 24th hours shifted and a return to basal values after 48 hours. Moreover,the eosinophils increase seems to prevent the increase of Nitric oxide thus confirming that in bronchial asthma eNo is a sign of airway eosiniphilia. The increase in eosinophils in sputum and the belated one in exhaled eNo are typical of patients developing an asthmatic reaction as these changes have not been osbserved either in control patients or in those with rhinitis from ysocianates. The pH of the condensate in the exhaled breath does not associate with variations linked to the asthmatic reaction induced by isocyanates.
Consequently isocyanates somehow seem to alter the ph circadian rhythm.
To conclude, patients with bronchial asthma from isocyanates showed a CC16 basic value higher both in the serum and urine pre-exposure with respect to control subjects, which suggests that in asthma there is an alteration of the bronchiolar epithelium in basic situations. A severe exposition to ysocianates does not imply meaningful variations of CC16 in serum and urine.

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EPrint type:Ph.D. thesis
Tutor:Maestrelli, Piero
Data di deposito della tesi:2008
Anno di Pubblicazione:2008
Key Words:asma occupazionale, espettorato indotto, ossido nitrico esalato, pH condensato, CC16 sierica ed urinaria
Settori scientifico-disciplinari MIUR:Area 06 - Scienze mediche > MED/44 Medicina del lavoro
Struttura di riferimento:Dipartimenti > pre 2012 Dipartimento di Medicina Ambientale e Sanità pubblica
Codice ID:566
Depositato il:24 Nov 2008
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