Reports of rapamycin-covered stents

Searching for treatment alternatives, we hypothesized that the basic pathogenesis of our patient’s condition might just be equivalent to that suggested for the coronary arteries restenosis; we suspected that in both conditions a similar mechanism of response to injury, manifested by exaggerated proliferation of either neoin-tima or granulation tissue around the disrupted epithelium. Encouraged by the seemingly effective endovascular procedure, we offered the patient endobronchial HDR brachytherapy. Early reports of rapamycin-covered stents used in coronary revascularization are promising in preventing neointimal growth, and it will be most interesting to examine their use in endobronchial stents.

rapamycin
rapamycin

The first report on the use of endobronchial HDR brachytherapy for nonmalignant causes, still in press at the time the treatment of our first patient was tailored, was done by Kennedy. In this report, a similar approach was chosen in two patients with lung transplantation, in whom hyperplastic bronchial obstruction developed at the site of the anastomosis, and in whom balloon dilatation, laser application, and stent placement failed to restore protracted patency. This group used a lower dose (3 Gy) than we did, although in one patient two sessions were required. The authors described a significant clinical improvement and patent airways, 6 months and 7 months after the procedure, in both patients.

Both reports, that of Kennedy and the present study, demonstrate the effectiveness of endobronchial HDR brachytherapy in preventing granulation tissue formation reactive to a bronchial stent. In spite of the impressive clinical results, data regarding the potential mechanism underlying these phenomena are still scarce. This is even more surprising considering the enthusiasm surrounding the congruent endovascular brachytherapy field, which has resulted in various clinical and laboratory studies. Indeed, clues regarding the biological effects of irradiation on the injured epithelium covering the bronchial wall emerge almost exclusively from the vascular model.

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Nasal Allergen Challenge: Systemic Effects

Airway inflammation and remodeling can be present in the lower airways of patients with allergic rhinitis, although it is less intense than in patients with asthma. During natural exposure, both the nose and lung come into contact with airborne allergens. Nasal inflammation may influence lower airway inflammatory processes by the release of inflammatory mediators into the circulation or through an effect on BM progenitors or inflammatory cells.  Nasal Allergen Challenge Systemic Effects

As most clinical trials have been performed during natural allergen exposure, studies evaluating the influence of upper airway disease on lower airways cannot properly assess the influence of nasal inflammation on lower airways. Provocative nasal allergen challenge has been used to help sort out the influences of allergic rhinitis on lower airways and specifically determine the influence of the upper airways on lower airway inflammation. Braunstahl performed nasal allergen provocations in allergic rhinitic patients without asthma and in normal control subjects.

An increase of eosinophils as well as increased expression of intercellular adhesion molecule-1 was observed in the nasal and bronchial biopsies of allergic rhinitic patients compared with control subjects. However, Beeh observed no significant difference in sputum eosinophils following nasal allergen provocation, although sputum ECP and intercellular adhesion molecule were increased. In addition, Braunstahl have shown that segmental bronchial allergen challenge can produce nasal eosinophilic inflammation.

Nasal Allergen Challenge: Systemic Effects

In this regard, we recently performed a study using repeated nasal challenges to determine if this can induce lower airway inflammation and to obtain a more accurate model of allergen exposure. Our preliminary results show that a large number of patients with allergic rhinitis with or without asthma can have significant lower airway inflammation after repeated nasal challenge.

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Hemopoietic Processes as Targets of Therapy

While intranasal steroids can improve lower airway hyperresponsiveness, a greater benefit is seen in patients with both allergic rhinitis and asthma if topical steroids are delivered to both sites of inflam-mation. Of less remarkable but still significant clinical benefit, working through a different pathway, montelukast, a specific leukotriene receptor antagonist (LTRA), has been shown to reduce allergic rhinitis and asthma symptoms. Cysteinyl leuko-trienes (CysLTs) are potent receptor agonist mediators capable of inducing cell recruitment and bronchospasm, increased vascular permeability, and nasal airway resistance. Hemopoietic Processes as Targets of Therapy

Table 1—Effects of Several Antiallergic Treatment Options on Hemopoietic Processes and Eosinophils

Treatment Sputum

Eosinophils

Nasal

Eosinophils

Eo/B

Progenitors

Antihistamine Uncertain Reduce/no effect Reduce
LTRA Reduce Reduce Reduce
Topical steroid Reduce Reduce Reduce
Systemic steroid Reduce Reduce Uncertain

Montelukast antagonizes these effects and thus attenuates the allergen-induced early and late asthmatic responses. It also reduces sputum eosinophilia following allergen challenge. Since CysLT receptors are expressed on hemopoietic progenitors, antagonism with montelukast may attenuate tissue eosinophilia via a systemic antiinflammatory effect (see below).

Hemopoietic Processes as Targets of Therapy

Modulation of Eosinophil Differentiation by CS

Hemopoietic mechanisms can be targeted by antiallergic therapies (Table 1). For example, topical treatment with CS can affect the hemopoietic response by abrogation of cytokine production by airways tissues, reduction in peripheral blood Eo/B progenitors, and decreases in BM myeloid progenitors (in a canine asthma model). Most likely, inhaled CS in these models exert their effects on the marrow progenitor response indirectly by interfering with cytokines elaborated from the inflamed tissue, which can then act systemically on the BM. However, a direct effect on progenitors cannot be excluded because there is evidence that, both in vitro and in vivo, low systemic levels of CS (10~9 mol/L) can block differentiation of the Eo/B progenitor in humans and of the myeloid progenitor in dogs.