G.U. Di Maria

Regulation of airway neurogenic inflammation by neutral endopeptidase

Airway neurogenic inflammation is caused by tachykinins released from peripheral nerve endings of sensory neurons within the airways, and is characterized by plasma protein extravasation, airway smooth muscle contraction and increased secretion of mucus. Tachykinins are degraded and inactivated by neutral endopeptidase (NEP), a membrane-bound metallopeptidase, which is located mainly at the surface of airway epithelial cells, but is also present in airway smooth muscle cells, submucosal gland cells and fibroblasts. The key role of NEP in limiting and regulating the neurogenic inflammation provoked by different stimuli has been demonstrated in a large series of studies published in recent years. It has also been shown that a variety of factors, which are relevant for airway diseases, including viral infections, allergen exposure, inhalation of cigarette smoke and other respiratory irritants, is able to reduce NEP activity, thus enhancing the effects of tachykinins within the airways. On the basis of these observations, the reduction of neutral endopeptidase activity may be regarded as a factor that switches neurogenic airway responses from their physiological and protective functions to a detrimental role that increases and perpetuates airway inflammation. However, further studies are needed to assess the role of neutral endopeptidase down regulation in the pathogenesis of asthma and other inflammatory airway diseases.

Sleep-related hypoxaemia and excessive erythrocytosis in Andean high-altitude natives

To determine whether nocturnal hypoxaemia contributes to the excessive erythrocytosis (EE) in Andean natives, standard polysomnographies were performed in 10 patients with EE and in 10 controls (mean haematocrit 76.6±1.3% and 54.4±0.8%, respectively) living at an altitude of 4,380 m. In addition, the effect of O2 administration for 1 h prior to sleep, and the relationship between the hypoxic/hypercapnic ventilatory response and the apnoea/hypopnoea index (AHI) during sleep were studied. Awake arterial oxygen saturation (Sa,O2) was significantly lower in patients with EEthan in controls (83.7±0.3% versus 85.6±0.4%). In both groups, the mean Sa,O2 significantly decreased during sleep (to 80.0±0.8% in EE and to 82.8±0.5% in controls). The mean Sa,O2 values remained significantly lower in patients with EE than in controls at all times of the night, and patients with EE spent significantly more time than the controls with an Sa,O2 of <80%. There were no differences between the two groups in the number and duration of the apnoeas/hypopnoeas. None of these variables were affected by O2 administration. In both groups the AHI positively correlated with the hypercapnic ventilatory response. Andean natives undergo minor respiratory disorders during sleep. The reduction inoxygen saturation found in subjects with excessive erythrocytosis was small, yet consistent and potentially important, as it remained below the threshold known for theincrease in erythropoietin stimulation. This may be an important factor promoting erythropoiesis, but its relevance needs to be further explored.

Role of endogenous nitric oxide in asthma

Endogenous nitric oxide (NO) is an ubiquitous signaling molecule with important regulatory functions such as regulation of blood pressure, neurotransmission, and host and immune defense. In the respiratory tract, NO is formed and released by various sources including endothelial and epithelial cells, nerves, airway smooth muscle, and inflammatory cells. Recent evidence suggests that endogenous NO is the neurotransmitter of the nonadrenergic noncholinergic inhibitory (iNANC) system, the only bronchorelaxant neural pathway of human airways. A number of studies also suggest that in some species epithelium‐derived NO accounts for the functional bronchoprotective role of the so‐called epithelium‐derived relaxing factor. In human airways, endogenous NO counteracts the bronchoconstriction induced by pharmacologic stimuli such as bradykinin, histamine, and methacholine. On the basis of these and other observations, it is suggested that a reduced synthesis and/or activity of endogenous NO may contribute to the pathogenesis of airway hyperresponsiveness that characterizes asthma and other respiratory disorders. This short paper summarizes the activities of endogenous NO in the airways of experimental animals and man, and discusses the evidence supporting the view that NO confers bronchoprotection.

Cerebral blood flow velocity after hyperventilation-induced vasoconstriction in hypertensive patients.

Background and Purpose: The aim of our study was to evaluate by transcranial Doppler ultrasonography the dynamics of blood flow velocity changes in the middle cerebral artery during and after hypocapniainduced vasoconstriction in untreated essential hypertensive patients. Methods: Sixteen hypertensive patients (10 men and six women, 29-62 years of age) and 10 healthy control subjects (six men and four women, 30-62 years of age) were studied. Patients with mild-tomoderate essential hypertension (mean±SE blood pressure, 171/106±3/2 mm Hg) belonged to stage I or II of the World Health Organization classification. Mean blood flow velocity in the middle cerebral artery, arterial blood pressure, and end-tidal CO2 partial pressure were recorded at baseline, during 2-minute hyperventilation, and every 30 seconds up to 5 minutes after hyperventilation. Results: End-tidal CO2 partial pressure values overlapped in the two groups throughout the study. Baseline values of mean blood flow velocity in hypertensive patients were similar to those in normotensive subjects (mean±SE values, 64.7±3.9 cm/sec versus 58.6±3.7 cm/sec). A similar fall in mean blood flow velocity was observed in hypertensive patients and normotensive subjects (43.2±2.8% versus 46.7±3.6%). Mean blood flow velocity reverted to baseline more quickly in hypertensive patients: 1.5 minutes after hyperventilation, mean blood flow velocity was 60.7±3.1% and 84.9±1.8% of control in normotensive subjects and hypertensive patients, respectively. No changes in arterial blood pressure were observed in either group throughout the study. Conclusions: This study demonstrates that the recovery of blood flow velocity in the middle cerebral artery after hyperventilation is faster in hypertensive patients than in normal subjects, thus providing further evidence that chronic hypertension is associated with changes in the dynamics of cerebral blood vessel reactivity.

Relationship between in vivo Airway Reactivity and in vitro Responsiveness of Tracheal Smooth Muscle in Inbred Rats

We evaluated the in vivo and in vitro airway responses to cholinergic stimulation in two highly inbred strains of rats. Five Fisher and six Lewis rats inhaled aerosols of doubling concentrations of methacholine (MCh). Pulmonary resistance (RL) was measured before and after each MCh inhalation. The concentration of MCh required to double RL (EC200RL MCh) was calculated. Spirally cut tracheal strips were suspended in an organ bath and the isometric tension was recorded. Cumulative concentration-response curves to carbachol were obtained using concentrations ranging from 10(-9) to 10(-3) M in half-log increments. The maximum tension (Tmax) developed and the negative log of the molar concentration required to induce 50% of Tmax (pD2) were calculated. The geometric mean of ED200RL MCh for the Fisher group was significantly lower than that for the Lewis group (0.68 and 2.66 mg/ml, respectively; p less than 0.05). No significant difference was found for Tmax (0.67 +/- 0.11 vs. 0.50 +/- 0.11 g) and pD2 value (6.24 +/- 0.08 vs. 6.21 +/- 0.22 -log M), indicating a similar contraction of tracheal smooth muscle. We therefore conclude that (1) in vivo airway responsiveness is strain-related and genetically determined in the rat; (2) that there is no correlation between in vivo and in vitro airway response to cholinergic stimulation and (3) that intrinsic properties of airway smooth muscle do not account for the differences observed in airway responsiveness in vivo.

Adenosine levels in the exhaled breath condensate: a potential surrogate marker of airway inflammation

To the Editor: We would like to congratulate Huszar et al. 1 on their important and meticulous study demonstrating elevated adenosine levels in the exhaled breath condensate of atopic asthmatic subjects compared to nonatopic controls. Their findings are in agreement with and somewhat complementary to previous data obtained from bronchoalveolar lavage fluid of patients with asthma and chronic obstructive pulmonary disease 2, thus adding to the …

Cyclooxygenase products mediate the cutaneous vasodilation induced by endothelin-1 in humans

Intradermal injection of endothelin-1 (ET-1) causes vasoconstriction (pallor) at the injection site, surrounded by a larger area of vasodilation (flare) in humans. Some of the vasomotor responses to ET-1 are thought to be mediated by prostaglandins. In the present study, we investigated the involvement of cyclooxygenase-derived products of arachidonic acid metabolism on the cutaneous vasomotor responses to ET-1. Ten normal subjects (25-44 years) were studied after treatment with either indomethacin (50 mg t.i.d.) or placebo according to a double blind cross-over design. Five doses of ET-1 (5 x 10(-5) to 5 x 10(-1) pmol) were injected intradermally 2 h after the last dose of indomethacin or placebo. Pallor and flare areas measured by planimetry 15 min after the injection were analyzed to evaluate cutaneous vasomotor responses to ET-1. ET-1 induced dose-dependent pallor and flare responses that were significant at the dose of 5 x 10(-3) pmol or greater. Indomethacin did not affect the ET-1-induced pallor but significantly shifted to the right the flare dose-response curve to ET-1. The inhibition of the flare response to 5 x 10(-1) pmol ET-1 was 58.9 +/- 8.5%. These results indicate that the cutaneous vasodilation induced by intradermal injection of ET-1 is mediated by the release of vasodilating cyclooxygenase products.

Allergen Inhalation Increases Cough Sensitivity in Subjects with Allergic Asthma

Non productive cough is a common symptom of bronchial asthma. In some asthmatic patients cough is the earlier and sometimes the only clinical manifestation of the disease. Therefore, it is reasonable to hypothesize that patients with bronchial asthma have a high sensitivity to cough stimuli. However, Bikerman and Barach (1) in their original study on cough induced by citric acid inhalation did not find any differences in cough sensitivity between normals and asthmatics. Similar results have been reported in more recent studies (2,3). Furthermore, cough response to capsaicin of asthmatic patients does not differ from that of normal subjects (4). In contrast with these observations, it has been reported that cough sensitivity to inhalation of acetic acid (5) or capsaicin (6) was greater than normal only in some asthmatic subjects but not in others. This discrepancy may have been due to the heterogeneity of the populations studied, which included non-allergic and allergic asthmatics. Furthermore, subjects with allergic asthma were sensitized to allergens with different seasonal distribution. Therefore, we hypothesized that allergen exposure increases airway sensitivity to cough stimuli in allergic asthmatic patients. To verify this hypothesis we evaluated the cough sensitivity to hypochloric iso-osmolar aerosols before and after allergen exposure in subjects with allergic asthma.

The Maximal Bronchoconstriction Induced by Methacholine is not Altered by Platelet Activating Factor

Airway hyperreactivity, which is a distinctive feature of asthmatic subjects, is characterized by a progressive reduction in airway caliber in response to bronchoconstrictive agents such as histamine or methacholine, and is depicted by a leftward shift of the dose-response curve. Furthermore, asthmatic subjects respond to increasing doses of histamine or methacholine with a progressive bronchoconstriction without reaching a maximal response (1). On the contrary, normal subjects have a limited bronchoconstriction and their dose-response curve reaches a plateau (1). This difference led to the hypothesis that in normal conditions there are physiological mechanisms that limit bronchoconstriction (2). It is believed that the absence of a maximal response in asthmatics is due to airway wall oedema and inflammation (2). In fact, it has been demonstrated that inhalation of leukotriene D4, which is known to increase airway vascular permeability, increases the maximal bronchoconstriction induced by methacholine in normal subjects (3).