Outcomes of Studies Concerning Patients with Asthma, Aspirin Intolerance, and Nasal Polyps

Of the seven patients with “triad” asthma, five had nasal biopsy specimens showing ciliated epithelium. One of the male patients with a nasal biopsy revealing only squamous metaplasia provided us with a semen sample. An additional patient had squamous metaplasia of the biopsied nasal mucosa, with rare ciliated cells identified only by light microscopy. Scanning and transmission electron microscopy of those specimens with ciliated epithelium obtained from these “triad” asthmatics all showed ultrastructurally normal cilia. Fig 1 (for left) is a diagramatic cross section of a cilium.

As shown in Fig 1 (center left), the central pair, nine peripheral doublets and dynein arms were present in their normal relationships. Sperm tails from the one “triad” asthmatic patient likewise were normal as were the nasal cilia from the control subjects. In contrast, about 46 percent of the cilia from the positive control patient with situs inversus and sinusitis showed one of two types of defects. Some showed microtubular transposition with absent central pair and others revealed ectopic microtubular placement with a normal number of microtubules (Fig 1 [center right]). In favorably oriented cross sections of cilia, dynein arms were visible on nearly all peripheral doublets. Some had shortened arms, and rarely the arms were not visible on a doublet. No cilia were seen with totally absent dynein arms. Individual shortened orxapparently absent dynein arms were seen in occasional cilia from our normal controls (Fig 1 [far right]), and so the significance of this finding is uncertain.

Patients with “triad” asthma

Light and phase contrast microscopy of the nasal biopsy specimen from the five “triad” asthmatic subjects and the two control specimens revealed normal-appearing function with good wave-like motion. Sperm obtained from one of the “triad” patients, as noted above, were motile. Ibis finding is consistent with the normal cilia seen in the other patients. In contrast, tissue from the patient with situs inversus and sinusitis revealed stifiE bristle-like cilia with little motion. The minimal motion observed occurred in a slow, stiff side-to-side pattern with little or no bending of the cilia.

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Hie pieces of ciliated tissue remained viable in tissue culture for as long as 20 weeks. Cultures were eventually discarded because of contamination by bacteria and/or fungi. Sections of tissue which were in culture for V/i months were stained with aqueous toluidine blue. These sections revealed uptake of the stain by the ciliated epithelium with little to no uptake in the underlying lamina propria, indicating viability of the ciliated epithelium despite necrosis of the underlying tissue. Small pieces of ciliated tissue from all of the “triad” asthmatics taken periodically from the larger specimens in culture were perfused with 2 jig/ml aspirin solution in phosphate buffered saline for 30 minutes without any perceptible change in ciliary motility; perfusion with 200 |xg/ml aspirin solution for 60 minutes also produced no observable change. Likewise, perfusion for 30 minutes with a solution containing a combination of aspirin 2 }ig/ml and arachidonic acid 2.66 xlO” M yielded no change in ciliary activity. Perfusion with aspirin also did not affect the ciliary activity of the control tissue from two patients undergoing nasal surgery for unrelated reasons.

In view of the report by Forrest et al that ATP and ATPase can enhance the activity of cilia from patients with the immotile cilia syndrome, nasal tissue cultures from our patient with situs inversus and sinusitis were perfused with 5×10 g/ml ATP or 2.38 xlO g/ml ATPase. Enhanced ciliary motion was observed in three and five different experiments, respectively, with either agent. The enhanced ciliary motion was reversed by washing out the cultures with Earle s balanced salt solution and could be restored by reperfusion with ATP or ATPase (Fig 2). Of note was the finding that not every cilium observed increased its motion with the perfusion of these solutions: some cilia (less than 30 percent) remained immotile. The ATP and ATPase had no definitive effect on the already active ciliary motion of the “triad” asthmatics and controls.

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Figure-1Figure 1. Far left, Diagram of cross section of cilium showing normal axoneme arrangement of nine outer microtubule doublets with inside and outside dynein arms and two central microtubules. Center left, Cilium from “triad” asthmatic patient with normal appearance. Center right, Ttoo cilia from patient with situs inversus and chronic sinusitis: one cilium with a 9 2 with translocation of a peripheral microtubular doublet and one cilium with a9 0 with translocation of a peripheral microtubular doublet arrangement. Far right, Cross sectional cilium from normal control patient with abnormal dynein arms (arrows) (original magnification x 110,000).

Figure-2Figure 2. Ciliary response to sequential administration of ATP and ATPase in patient with situs inversus. Median ciliary motility was scored in a manner similar to Forrest et al.“The initial, small enhancement in ciliary motion after simply perfusing with Earles solution may just reflect slight mechanical stimulation from the medium perfusing the chamber and/ or the increase in temperature in the chamber from room temperature to 37° C.