New insights into pulmonary hemorrhage

In this issue of Pediatric Investigation, Tang et al1 describe a cohort of pediatric patients with interstitial lung disease associated with heterozygous SFTPC mutations, with the goal of highlighting disease manifestations and clinical outcomes related to surfactant protein C (SP‐C) deficiency. A subgroup of patients with pulmonary hemorrhage were identified which may offer new pathophysiological insights. Pulmonary hemorrhage is a heterogeneous disease group ranging from anti‐neutrophil cytoplasmic antibodies positive vasculitis and lupus associated disease to primary pulmonary hemosiderosis. A cellular understanding of pulmonary hemosiderosis is lacking.2

SFTPC‐associated surfactant deficiency is an autosomal dominant monogenic cause of interstitial lung disease, causing a range of pulmonary symptoms.3, 4 The most commonly identified mutation in SFTPC is a missense change, annotated I73T in the literature and accounting for about 30% of all cases. It is associated with a range of clinical presentations. Tang et al1 highlight the findings of pulmonary hemorrhage and auto‐antibodies, and even a family history of rheumatoid arthritis in one patient's father, who also carried the mutation. This finding supports that SFTPC mutations have variable phenotypic expressivity, which can include pulmonary hemorrhage. Additionally, the authors report that these two patients responded well to treatment with hydroxychloroquine.

These features of pulmonary hemorrhage and auto‐immunity have recently been described in another condition, COPA syndrome.2, 5 COPA syndrome, which is named for the gene that is mutated (coatomer protein complex alpha: COPα), is typically associated with arthritis and pulmonary hemorrhage. The COPA gene regulates intracellular transport, playing a key role in protein synthesis and packaging. The COPA I complex, which includes the COPα protein, mediates retrograde transport from the Golgi back to the rough endoplasmic reticulum (ER). As such, it regulates the transport of misfolded proteins back to the ER for reprocessing or into lysosomes for destruction. In COPA syndrome, there is a defect in protein transport, which results in significant ER stress. ER stress in the alveolar epithelium or immune cells is likely to be central to the pathophysiology of pulmonary hemorrhage. In COPA syndrome, there is an immune defect, which causes increased numbers of Th17 cells and pro‐inflammatory cytokine expression, including IL‐1β and IL‐6. This immune defect could be causative for pulmonary hemorrhage but is unlikely to be the whole story as lung biopsies from these patients lack significant inflammatory signatures. ER stress in epithelial cells such as type II pneumocytes is hypothesized to be central to the pathophysiology of pulmonary hemorrhage.

Mutations in SFTPC are known to cause interstitial lung disease with a wide spectrum of pathology.4 Pulmonary hemorrhage is now a recognized feature. This description by Tang et al offers further supporting evidence that ER stress in alveolar epithelium is central to pulmonary hemorrhage. SFTPC encodes a large 21‐kD precursor protein, which is proteolytically processed to the 3.7‐kD mature hydrophobic form. It is packaged in the lamellar body and subsequently secreted into the airspace with surfactant protein B and phospholipids. The larger precursor protein has a key domain, the BRICHOS domain that is necessary for the transport/chaperoning of the hydrophobic protein across the trans‐Golgi network. More than 60 mutations in SFTPC have been identified in patients with interstitial lung disease. The majority of reported mutations are located in the BRICHOS domain. Several studies of BRICHOS mutations demonstrated an accumulation of misfolded proSP‐C in the rER and Golgi, which triggers ER stress and apoptosis. The common I73T mutation is in the linker region between the BRICHOS domain and the mature protein. This mutation interferes with autophagic vesicle formation resulting in the accumulation of large intracytoplasmic vacuoles in the cell. Mechanistically, the I73T mutation results in significant ER stress. The response to hydroxychloroquine, a potent inhibitor of autophagy, is intriguing.

As SP‐C's expression is confined to type II pneumocytes, these cells are central to the pathology of pulmonary hemorrhage. Indeed, the health of these cells is central to the integratory of pulmonary epithelium. SFTPC mutations that lead to ER stress can cause pulmonary interstitial lung disease and have now been associated with pulmonary hemorrhage. This case series adds to our understanding of the role of ER stress in type II pneumocytes in lung disease.

CONFLICT OF INTEREST

None.

Yonker LM, Hawley M, Kinane TB. New insights into pulmonary hemorrhage. Pediatr Invest. 2019;3:207‐208. 10.1002/ped4.12170