Interstitial pneumonia in Hermansky-Pudlak syndrome: significance of florid foamy swelling/degeneration (giant lamellar body degeneration) of type-2 pneumocytes

Abstract

Although usual interstitial pneumonia (UIP)-like IP has been known as the most serious complication of Hermansky-Pudlak syndrome (HPS), its pathologic features and pathogenesis are poorly understood. We investigated biopsied and autopsied lung tissues from five patients who died of UIP-like IP associated with HPS (HPSIP). The salient histopathologic features of HPSIP observed were: (1) alveolar septa displaying florid proliferation of type-2 pneumocytes (2PCs) with characteristic foamy swelling/degeneration; (2) patchy fibrosis with lymphocytic and histiocytic infiltration centered around respiratory bronchioles, occasionally showing constrictive bronchiolitis; and (3) honeycomb change without predilection for the lower lobes or subpleural area. Those peculiar 2PCs were histochemically characterized by the over accumulation of phospholipid, immunohistochemically by a weak positivity for surfactant protein, and ultrastructurally by the presence of numerous giant lamellar bodies that compressed the nucleus with occasional cytoplasmic disruption, together suggesting a form of cellular degeneration with an over accumulation of surfactant (giant lamellar body degeneration). The present study strongly indicates that there is a basic defect in the formation/secretion process of surfactant by the 2PCs in HPS, which may well be the triggering factor for the HPSIP development. Other factors, such as macrophage dysfunction, may be working synergistically for further acceleration of the inflammatory process.

Evolving Concepts of Apoptosis in Idiopathic Pulmonary Fibrosis

“…Interestingly, mutations in the surfactant SP-C gene are associated with familial desquamative and nonspecific interstitial pneumonitis in children and UIP in adults. A similar defect in surfactant processing and secretion appears to result in "giant lamellar body degeneration" of type II AECs observed in the HermanskyPudlak syndrome, which is associated with mutations in the Hermansky-Pudlak syndrome-1 gene and interstitial pneumonia (43). The potential role of defects in protein processing and trafficking in sporadic cases of IIPs is unknown; these observations, nonetheless, reinforce the importance of gene-environment interactions in the expression of varied host tissue reactions and phenotypes.…”

Early Alveolar Epithelial Dysfunction Promotes Lung Inflammation in a Mouse Model of Hermansky-Pudlak Syndrome

“…Pulmonary findings commonly described in adults with HPS from case series and case reports include macrophage-predominant inflammation, ceroid deposits within macrophages, and progressive honeycombing on highresolution computed tomography indicative of progressive pulmonary fibrosis (3,33,34). Longitudinal studies establishing the natural history of HPS lung disease are limited and have included only adults after presentation with restrictive lung remodeling.…”

“…The surfactant-containing lamellar body exhibits an acidic pH, undergoes regulated secretion, and possesses lysosomal transmembrane proteins in the limiting membrane, notably Lamp1 and Lamp3. Autopsy studies of adults with HPS have demonstrated foamy degeneration of alveolar type 2 cells as well as hyperplasia, alveolar inflammation, and pulmonary fibrosis (3). Mouse models of HPS, including the mouse homologs of HPS1 (pale ear) and HPS2 (pearl), similarly display foamy degeneration of alveolar type 2 cells of adult animals.…”

Hermansky-Pudlak Syndrome with a Novel Mutation

“…It possibly results from a defect in a protein required for the biogenesis, structure, or function of these various membrane-bound organelles. Idiopathic pulmonary fibrosis-like interstitial pneumonia has been known to be the most serious complication of HPS (7), and possible association of pulmonary inflammatory cell dysfunction, including alveolar macrophage, with the pathogenesis of interstitial pneumonia in HPS has been suggested (20,21). However, its detailed molecular pathogenesis remains unknown.…”