The proteostasis network consists of a large number of specialized proteins that are necessary for the precise function of processes that oversee the life cycle of all cellular proteins (1). Newly translated proteins are folded into their native state through the action of molecular chaperones, and trafficked to specific subcellular locations. Proteins that are damaged or not needed are degraded via the ubiquitin proteasome or lysosomal degradation systems (2). Disruption of the proteostasis network at any point presents a major challenge to the intracellular proteome, simultaneously causing a relative imbalance in functional levels of critical proteins in subcellular compartments and the accumulation of misfolded or damaged proteins that are prone to aggregate or precipitate in the remarkably protein-rich intracellular environment (3).

In humans, the molecular" chaperome" is comprised of some 332 genes that serve promiscuous roles in protein folding (4). These chaperones include canonical members of the heat shock protein (HSP) family as well as proteins involved in organellespecific folding in the endoplasmic reticulum and the mitochondria. Chaperones are expressed continuously in most cells but are robustly induced upon environmental (eg, heat shock) or organelle-specific stress (eg, endoplasmic reticulum stress or the mitochondrial unfolded protein response). Genetic studies hint at proteostatic stress in the lung epithelium as a potential driver of many lung diseases, including pulmonary fibrosis (5, 6). For example, mutations in the gene encoding SFTPC that cause misfolding of the protein have been observed in families with increased rates of idiopathic pulmonary fibrosis (7). An autosomalrecessive mutation that results in a defect in vesicular trafficking results in Hermansky-Pudlak syndrome, which is associated with highly penetrant pulmonary fibrosis (8). Although direct evidence of a protein folding defect has not been shown, a common variant SNP in the promoter region of the gene encoding an abundantly expressed mucin, MUC5B, is associated with increased expression of the protein and an increased risk of pulmonary fibrosis (9). The chronic proteostatic stress associated with these mutations might be expected to induce the expression of chaperones in the lung as part of an adaptive response. Consistent with this hypothesis, genetic loss of HSP70 (Hspa1a) in mice has been reported to increase susceptibility to bleomycin-induced fibrosis (10). In this issue of the Journal, Sellares and colleagues (pp. 629-636) report on the expression of HSP70 in lung tissues and primary human lung fibroblasts obtained from patients with pulmonary fibrosis (11). Contrary to predictions, the expression of constitutive and inducible HSP70 was reduced in lung tissue from patients with pulmonary fibrosis compared with normal control subjects and in primary cultured fibroblasts from the lungs of patients with pulmonary fibrosis. The investigators go on to show that administration of the profibrotic cytokine TGF-b or viral transfection of IGFBP5 reduced the expression of both constitutive