Over the past decade, it has become increasingly recognized that airways inflammation is one of the major components of asthma. Until recently, measurements of bronchial responsiveness and mediators of allergic reactions were the only methods of studying pathogenetic mechanisms in asthma. With improved diagnostic procedures such as fiberoptic bronchoscopy, it has become possible to investigate these mechanisms and the resulting inflammatory changes in situ. BAL has highlighted the presence of mast cells and eosinophils and has given proof of their mediator participation in airways inflammation and hyperresponsiveness. Endobronchial biopsies have so far yielded results that are similar to those obtained from postmortem studies, although it appears that there are varying degrees of inflammation in living asthmatics. Even in mild disease, the histopathologic features of bronchial asthma are consistent with chronic inflammation. Indirect evidence obtained from allergen challenge leading to increased bronchial hyperresponsiveness during LAR, and direct evidence of inflammatory cells and their mediators in the airway mucosa and lumen after allergen challenge argue for an active role of cells in bringing about inflammatory changes. At present, however, it is not possible to relate precisely the findings obtained by bronchoscopy to the clinical presentation and progression of asthma. Cell activation with production of potent mediators of inflammation may be more relevant to inflammation than the simple presence of these cells in the airways. Almost all the inflammatory cells present in the bronchial wall and lumen have been implicated in the pathogenesis of mucosal inflammation in asthma, but with our current state of knowledge, none can be singled out as the most important contributor. The mast cell was the first to be investigated in depth, and despite the accumulation of large amounts of data concerning its ultrastructure and function, it remains uncertain to what extent this cell is involved in inflammatory responses. Thus, while its main role appears to be that of initiator of allergen-induced responses, the eosinophil has attracted more attention as a proinflammatory cell rather than as an antiinflammatory cell with a capacity to be selectively recruited from the circulation in response to IgE-dependent signals. The eosinophil secretes potent mediators that cause damage to the bronchial epithelium and lead to bronchoconstriction. The role of other cells is at present not as well defined.(ABSTRACT TRUNCATED AT 400 WORDS)

Mucosal inflammation in asthma.

Previous studies of single families have suggested that familial factors may be important in the pathogenesis of obstructive sleep apnea. In this report, the role of inheritance in obstructive sleep apnea was assessed by quantitating the degree of familial clustering of symptoms associated with sleep-related breathing disorders. In total, 272 subjects from 29 families Identified through an Index case with obstructive sleep apnea and 21 control families with no relative known to have sleep apnea were studied with questionnaires that ascertained health status and symptoms. The unadjusted odds ratios of habitual or disruptive snoring, breathing pauses, and excessive daytime sleepiness in subjects with a single relative with the same symptom were 1.40 to 1.53 (p < 0.05). Odds ratios increased progressively for subjects with increasing numbers of symptomatic relatives (for example, 2.77 to 3.71 for subjects with three symptomatic relatives). Adjustment for body mass index, age, and gender modestly reduced thes...

Studies in the genetics of obstructive sleep apnea. Familial aggregation of symptoms associated with sleep-related breathing disturbances.

Eosinophils were first clearly identified by Ehrlich in 1879 (56) and the association of increased numbers of blood eosinophils with asthma was soon recognized (33). It is now well established that large numbers of eosinophils, together with mononuclear cells, are frequently present in and around the bronchi of patients who have died from asthma (31), CharcotLeyden-crystals (CLC) are another well-known eosinophil associated feature of the asthma process, which has now been identified as membrane-derived lysophospholipase (118), There has been a continuing debate regarding the role of eosinophils in asthma. In short, do they ameliorate the inflammatory process or promote it (117)? On the one hand eosinophil-derived products biodegrade mediators such as the peptide leukotrienes, which comprise the slow-reacting substance of anaphylaxis (leukotriene (LT) C4, D ,̂ E^). This is achieved through both oxidation to their respective sulphoxides and by conversion to the 6-trans diastereoisomers of leukotriene (LT) B4 by granule-derived eosinophil peroxidase (54, 119). The original observation that eosinophil-derived arylsulphatase could deactivate SRS-A was probably due to biodegradation of LTC4 to LTE4 by contaminating dipeptidases (73, 114). Similarly eosinophils also contain histaminase located in the granule compartment which oxidizes histamine to its catabolite imidazole acetic acid (121). However, in recent years increased understanding of the biology of the eosinophil, particularly with regard to their granule and membrane-derived products, has emphasized a pro-inflammatory rather than homeostatic role for this cell type. Many investigators now believe that eosinophils are a major effector of tissue damage in asthma (63), Several recent clinical studies, particularly those involving bronchoalveolar lavage, have provided more direct evidence to support this concept. The purpose of this review is to examine some recent findings on the biology of the eosinophil which might be relevant to the role of this cell in asthma and to evaluate various clinical studies which have identified an association between eosinophils, the late-phase response to antigen challenge, non-specific bronchial hyperreactivity and day-to-day asthma. All the work referred to has been performed on human eosinophils unless otherwise stated.

The role of the eosinophil in the pathogenesis of asthma

Hypercapnia observed in patients with chronic respiratory failure may not be an ominous sign for prognosis when they are receiving long-term oxygen therapy (LTOT). In this study, we selected 4,552 patients with chronic obstructive pulmonary disease (COPD) and 3,028 with sequelae of pulmonary tuberculosis (TBsq) receiving LTOT from 1985 to 1993 throughout Japan and prospectively analyzed their prognoses. The hypercapnic patients (PaCO2 >= 45 mm Hg) had a better prognosis than the normocapnic patients (35 = 65 mm Hg against normocapnic patients. This favorable effect of hypercapnia in TBsq was particularly apparent in the patients without severe airway obstruction. Even a rise of 5 mm Hg or more in PaCO2 over the initial 6- to 18-mo follow-up period was not associated with poor prognosis in TBsq, although it was in COPD. From these findings, we conclude that hypercapnia should not be generally considered an ominous sign for prognosis in those patients who receive LTOT.

Prognostic Value of Hypercapnia in Patients with Chronic Respiratory Failure during Long-term Oxygen Therapy

A Family Study of Sleep Apnea: Anatomic and Physiologic Interactions

To determine whether abnormal chemical drives to breathe in patients with chronic obstructive pulmonary disease (COPD) antedate the development of chronic CO2 retention, we measured ventilatory and P0.1 responses to hypercapnia and hypoxia in 14 such patients and 23 of their normal adult offspring. Hypoxic responses in the patients were positively correlated with the mean hypoxic responses of their offspring. Neither the hypercapnic responses nor the resting breathing patterns of the patients were related to those of their offspring. Hypoxic response was lower in offspring of hypercapnic patients than in offspring of normocapnic patients. Blunt hypoxic responses in patients with COPD are influenced by familial factors and may represent a premorbid “risk factor” in the development of CO2 retention in this disease. This does not appear to be true for hypercapnic response or breathing pattern.

Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease.

To evaluate the contribution of vagal airway receptors to ventilatory control during hypercapnia, we studied 11 normal humans. Airway receptor block was induced by inhaling an aerosol of lidocaine; a preferential upper oropharyngeal block was also induced in a subgroup by gargling a solution of the anesthetic. Inhalation of lidocaine aerosol adequate to increase cough threshold, as measured by citric acid, did not change the ventilatory response to CO2, ratio of the change in minute ventilation to change in alveolar PCO2 (delta VI/delta PACO2), compared with saline control. Breathing pattern at mean CO2-stimulated ventilation of 25 l/min showed significantly decreased respiratory frequency, increased tidal volume, and prolonged inspiratory time compared with saline. Resting breathing pattern also showed significantly increased tidal volume and inspiratory time. In nine of the same subjects gargling a lidocaine solution adequate to extinguish gag response without altering cough threshold did not change delta VI/delta PACO2 or ventilatory pattern during CO2-stimulated or resting ventilation compared with saline. These results suggest that lower but not upper oropharyngeal vagal airway receptors modulate breathing pattern during hypercapnic as well as resting ventilation but do not affect delta VI/delta PACO2.

Effects of upper or lower airway anesthesia on hypercapnic ventilation in humans.

Because pulmonary resection decreases pulmonary compliance, the effects of resection on ventilation might be similar to the known effects of elastic loading. We evaluated the breathing pattern and ventilatory drive in 12 patients before and after pulmonary resection with mean tissue loss of 4 segments. During resting ventilation, the only significant change after resection was a decrease in inspiratory time (Tl). At a higher level of minute ventilation (VE), induced by CO2 rebreathing, significant changes included increased respiratory frequency, decreased tidal volume and Tl, and increased occlusion pressure (P0.1). Both ventilation and occlusion pressure responses to CO2 (delta VE/delta PACO2, delta P0.1/delta PACO2) were unchanged after resection. We conclude that increased ventilation induced by CO2 rebreathing unmasks a breathing pattern after pulmonary resection which is similar to that seen with breathing against an external elastic load.

Ventilatory control after pulmonary resection.

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Familial aspects of ventilatory control in patients with chronic obstructive pulmonary disease.

Effects of upper or lower airway anesthesia on hypercapnic ventilation in humans.

Ventilatory control after pulmonary resection.