Pulmonary Neuroendocrine Cells (PNECs)

Introduction: Cells showing neuroendocrine differentiation (PNECs or Kulschitzky cells) are present in the normal airway epithelium of human and animal lungs. These cells have immunohistochemical reactivity and ultrastructure similar to those of neuroendocrine tumors. In certain conditions, the cells undergo hyperplasia confined to the epithelium.

Normal PNECs: In the fetus, these cells occur as clusters--neuroepithelial bodies--which are innervated. Contrary to general belief, PNECs are also present in the adult although usually as single cells. Chromogranin A appears to be the most sensitive immunohistochemical marker to identify them. In a study of normal adult human lungs, the fraction of PNECs among lining epithelial cells in both large and small conducting airways was similar at 0.41%. A measure of the proliferative rate for PNECs indicated that it was similar to that of other epithelial cells (about 1%) [1]. In another study of whole-mount preparations of a major axial rat airway, there were greater numbers of PNECs in proximal airway generations than in distal ones. However, their number and distribution did not differ between neonates and adults. At bifurcations, PNECs tended to occur on carinas rather than on lateral walls [2].

Function of PNECs: In the fetal rabbit, an oxygen-sensing mechanism has been found that provides evidence that, like the carotid body, these cells function as chemoreceptors [3]. In the fetal mouse, bombesin, which is similar to gastrin-releasing peptide of mamalian PNECs, was shown to stimulate airway branching in culture, suggesting the importance of these cells in lung development [4].

Hyperplasia of PNECs: PNECs have been noted to be hyperplastic in neonatal bronchopulmonary dysplasia [5], in infants with congenital diaphragmatic hernia [6], and in hyperoxic or hypoxic conditions in rats [5]. Hyperplasia has been reported in persons living at high altitude and in cigarette smokers [7]. Certain other lung diseases--primary pulmonary hypertension [8], carcinoid tumors [9], cystic fibrosis, asthma, panbronchiolitis, COPD, and eosinophilic granuloma--are also associated with PNEC hyperplasia; and in a few cases, it appears that the hyperplasia may actually cause airway disease [7].

Normal PNECs: In normal, adult human lungs, PNECs react with antibodies to chromogranin A, gastrin releasing peptide, calcitonin, and protein gene product 9.5, but are best demonstrated with antibodies to chromogranin A, as shown in the photo (two brown-stained cells). In adults, PNECs normally occur as single cells [1].

References

1. Boers J, den Brok J, Koudstaal J, Arends J, Thunnissen F. Number and proliferation of neuroendocrine cells in normal human airway epithelium. Am J Respir Crit Care Med 1996; 154:758-763.

2. Avadhanam K, Plopper C, Pinkerton K. Mapping the distribution of neuroepithelial bodies of the rat lung. A whole-mount immunohistochemical approach. Am J Pathol 1997; 150:851-859.

3. Youngson C, Nurse C, Yeger H, Cutz E. Oxygen sensing in airway chemoreceptors. Nature 1993; 365:153-155.

4. King K, Torday J, Sunday M. Bombesin and [Leu8]phyllolitorin promote fetal mouse lung branching morphogenesis via a receptor-mediated mechanism. Develop Biol 1995; 92:4357-4361.

5. Shenberger J, Shew R, Johnson D. Hyperoxia-induced airway remodeling and pulmonary neuroendocrine cell hyperplasia in the weanling rat. Pediatr Res 1997; 42:539-544.

6. Ijsselstijn H, Gaillard J, De Jongste J, Tibboel D, Cutz E. Abnormal expression of pulmonary bombesin-like peptide immunostaining cells in infants with congenital diaphragmatic hernia. Pediatr Res 1997; 42:715-720.

7. Aguayo S, Miller Y, Waldron Jr J, Bogin R, Sunday M, Staton Jr G, Beam W, King Jr T. Idiopathic diffuse hyperplasia of pulmonary neuroendocrine cells and airways disease. N Engl J Med 1992; 327:1285-1288.

8. Heath D, Smith P, Gosney J, Mulcahy D, Fox K, Yacoub M, Harris P. The pathology of the early and late stages of primary pulmonary hypertension. Br Heart J 1987; 58:204-213.

9. Miller R, Müller N. Neuroendocrine cell hyperplasia and obliterative bronchiolitis in patients with peripheral carcinoid tumors. Am J Surg Pathol 1995; 19:653-658.

Discussion

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