SNARE proteins, in particular syntaxin 2 and SNAP 23, are required for regulated surfactant sellckchem secretion. Both proteins are associated with the plasma membrane and to some degree with lamellar bodies. In parallel to secretion, AECII reinternalize and recycle surfactant components from the alveolar surface by means of endocytosis via clathrin dependent and clathrin inde pendent pathways, which include routing to early endo somes and multivesicular bodies. Interstitial lung disease is a heterogeneous group of diseases of known and unknown etiology. Several histological and clinical subtypes of ILD are linked to the SP C protein deficiency caused by muta tions of the corresponding SFTPC gene. Many SP C mutations cluster within the preproteins BRICHOS domain and lead to misfolding of the preprotein, aber rant trafficking and processing.

To date, all affected individuals with BRICHOS domain mutations have been heterozygous with no detectable mature SP C in their lungs, suggesting a dominant negative effect of the mutant allele. Moreover, in cell lines expressing BRICHOS domain mutations, proSP C forms perinuclear aggregates, consistent with the cells inability to clear aggregated misfolded proteins and a toxic gain of function. Various pathologic mechanisms for these mutations causing chronic accu mulation of misfolded proSP C have been proposed, such as induction of endoplasmic reticulum stress, cytotoxicity, and caspase 3 and caspase 4 mediated apoptosis. These factors might contribute to ILD through cell injury and death of AECII.

In addition to the BRICHOS domain mutations, a second class of SFTPC mutations has emerged. AV-951 A heterozygous mis sense mutation, leading to a substitution of threonine for isoleucine at position 73 of the proSP C, is the most frequent SFTPC mutation. There is a strong variability in the phenotype of these patients, ranging from asymptomatic to early fatal cases. I73T SP C is marked by mistrafficking of the preprotein to the endosomal compartment and by preserved secre tion of both mature and aberrant proSP C and proSP B forms and their intra alveolar accumulation. Yet, current knowledge on SP CI73T lacks a precise understanding of the proSP C processing abnormalities, concurrent cell stress response and cytotoxicity, as well as perturbations of the surfactant composition and secretion.

Current treatment of the genetic interstitial lung dis eases in children is unfortunately empirical. Corticoster oids are anti inflammatory and stimulate surfactant protein Rucaparib transcription. Chloroquine and its less toxic derivative hydroxychloroquine are used and believed to act on the lysosomal function, i. e. reduce vesicle fusion, exocytosis and proteolytic degra dation or stimulate lamellar body biogenesis. Thus, there is a need to define the cellular mechanism of the currently applied treatments.