Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal disease for which no effective therapy exists to date. To identify the molecular mechanisms underlying IPF, we performed comparative proteome analysis of lung tissue from patients with sporadic IPF (n = 14) and human donor lungs (controls, n = 10) using two-dimensional gel electrophoresis and MALDI-TOF-MS. Eighty-nine differentially expressed proteins were identified, from which 51 were up-regulated and 38 down-regulated in IPF. Increased expression of markers for the unfolded protein response (UPR), heat-shock proteins, and DNA damage stress markers indicated a chronic cell stress-response in IPF lungs. By means of immunohistochemistry, induction of UPR markers was encountered in type-II alveolar epithelial cells of IPF but not of control lungs. In contrast, up-regulation of heat-shock protein 27 (Hsp27) was exclusively observed in proliferating bronchiolar basal cells and associated with aberrant re-epithelialization at the bronchiolo-alveolar junctions. Among the down-regulated proteins in IPF were antioxidants, members of the annexin family, and structural epithelial proteins. In summary, our results indicate that IPF is characterized by epithelial cell injury, apoptosis, and aberrant epithelial proliferation.
Hypoxia impairs alveolar fluid clearance by inhibition of Na+ reabsorption, and also impairs β 2 adrenergic signaling in alveolar epithelium. Since both are major rescue mechanisms preventing pulmonary edema, we studied whether acute and prolonged treatment with terbutaline would prevent hypoxic inhibition of ion transport. Short circuit currents (ISC) were measured on normoxic and hypoxic (1.5% O2; 24h) primary rat alveolar type II (ATII) cells in absence and presence of terbutaline (1 to 100 μM, 24h). Control and pre-treated cells were stimulated acutely with terbutaline. Transepithelial transport was measured as short circuit current (ISC) in Ussing chambers. Terbutaline induced a rapid decrease ISC (-20%) followed by a slow raise. The transient change in ISC was not inhibited by amiloride but was prevented after Cl- depletion indicating a Cl- current. The slow increase after this transient was amiloride-sensitive indicating a Na+ current. Total ISC, its amiloride-sensitive component, and the transient decrease upon terbutaline stimulation were decreased by hypoxia. 24h treatment with terbutaline stimulated these currents in normoxia and hypoxia, although stimulation was less in the latter. 24h treatment with terbutaline increased the capacity of Na+/K+-ATPase and ENaC as measured after permeabilization with amphotericin. These changes were not paralleled by altered mRNA expression. Acutely applied terbutaline induced a 4-fold increase in cAMP formation in normoxia; terbutaline-induced cAMP-formation was impaired by hypoxia (-20%). Pre-treatment with terbutaline for 24h decreased terbutaline-induced cAMP formation by 85%. Despite this desensitization, addition of terbutaline to terbutaline pre-treated cells caused a larger increase in Cl- and Na+ transport both in normoxia and hypoxia than in non pre-treated cells. These results indicate that β 2 adrenergic stimulation increased Na+- and Cl- transport in ATII cells even in hypoxia thus restoring normal reabsorption.
The activation of Endoplasmic Reticulum (ER) stress and Unfolded Protein Response (UPR) was first observed in patients with familial interstitial pneumonia (FIP) carrying mutations in the C-terminal BRICHOS domain of surfactant protein C (SFTPC). Here, aggresome formation and severe ER stress was demonstrated in type-II alveolar epithelial cells (AECII), which specifically express this very hydrophobic surfactant protein. In subsequent studies, FIP-patients with mutations in the gene encoding surfactant protein A2 (SFTPA2) were discovered, whose overexpression in epithelial cells in vitro also resulted in significant induction of ER stress. Moreover, prominent ER stress in AECII was also observed in FIP-patients not carrying the SFTPC/SFTPA2 mutations, as well as in patients with the more common sporadic forms of IP. Additionally, cases of adult-onset FIP with mutations in Telomerase genes and other telomereassociated components were reported. These mutations were associated with telomere shortening, which is a potential cause for triggering a persistent DNA damage response and replicative senescence in affected cells. Moreover, shortened telomeres were observed directly in the AECII of FIP-patients, and even sporadic IP cases, in the absence of any gene mutations. Here, we try to figure out the possible origins of ER stress in sporadic IP cases and non-SFTPC/SFTPA2-associated FIP.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.