Mutant surfactant A2 proteins associated with familial pulmonary fibrosis and lung cancer induce TGF-β1 secretion

Mutations in the genes encoding the lung surfactant proteins are found in patients with interstitial lung disease and lung cancer, but their pathologic mechanism is poorly understood. Here we show that bronchoalveolar lavage fluid from humans heterozygous for a missense mutation in the gene encoding surfactant protein (SP)-A2 (SFTPA2) contains more TGF-β1 than control samples. Expression of mutant SP-A2 in lung epithelial cells leads to secretion of latent TGF-β1, which is capable of autocrine and paracrine signaling. TGF-β1 secretion is not observed in lung epithelial cells expressing the common SP-A2 variants or other misfolded proteins capable of increasing cellular endoplasmic reticulum stress. Activation of the unfolded protein response is necessary for maximal TGF-β1 secretion because gene silencing of the unfolded protein response transducers leads to an ∼50% decrease in mutant SP-A2-mediated TGF-β1 secretion. Expression of the mutant SP-A2 proteins leads to the coordinated increase in gene expression of TGF-β1 and two TGF-β1-binding proteins, LTBP-1 and LTBP-4; expression of the latter is necessary for secretion of this cytokine. Inhibition of the TGF-β autocrine positive feedback loop by a pan-TGF-β-neutralizing antibody, a TGF-β receptor antagonist, or LTBP gene silencing results in the reversal of TGF-β-mediated epithelial-to-mesenchymal transition and cell death. Because secretion of latent TGF-β1 is induced specifi cally by mutant SP-A2 proteins, therapeutics targeted to block this pathway may be especially beneficial for this molecularly defined subgroup of patients.