Systematic review of drug effects in humans and models with surfactant-processing disease

Abstract

Fibrotic interstitial pneumonias are a group of rare diseases characterised by distortion of lung interstitium. Patients with mutations in surfactant-processing genes, such as surfactant protein C (SFTPC), surfactant protein A1 and A2 (SFTPA1 and A2), ATP binding cassette A3 (ABCA3) and Hermansky-Pudlak syndrome (HPS1, 2 and 4), develop progressive pulmonary fibrosis, often culminating in fatal respiratory insufficiency. Although many mutations have been described, little is known about the optimal treatment strategy for fibrotic interstitial pneumonia patients with surfactant-processing mutations.We performed a systematic literature review of studies that described a drug effect in patients, cell or mouse models with a surfactant-processing mutation. In total, 73 articles were selected, consisting of 55 interstitial lung disease case reports/series, two clinical trials and 16 cell or mouse studies. Clinical effect parameters included lung function, radiological characteristics and clinical symptoms, while experimental outcome parameters included chemokine/cytokine expression, surfactant trafficking, necrosis and apoptosis. SP600125, a c-jun N-terminal kinase (JNK) inhibitor, hydroxychloroquine and 4-phenylbutyric acid were most frequently studied in disease models and lead to variable outcomes, suggesting that outcome is mutation dependent.This systematic review summarises effect parameters for future studies on surfactant-processing disorders in disease models and provides directions for future trials in affected patients.

FIGURE 1

Flowchart of the article selection process. HPS: Hermansky–Pudlak syndrome.

FIGURE 2

Targets of drugs investigated in humans and disease models with a surfactant-processing mutation. Damage to alveolar tissue causes fibrogenesis, which can be targeted by drugs in multiple ways. Expanded section: alveolar type II cell (AEC2) with organelles involved in surfactant processing. MPS: methylprednisolone; SP: surfactant protein; LB: lamellar bodies; EE: early endosomes; MVB: multivesicular bodies; ER: endoplasmic reticulum; 4-PBA: 4-phenylbutyric acid; MCP: monocyte chemotactic protein; ERK: extracellular signal-regulated kinases; HCQ: hydroxychloroquine; AZA: azathioprine; AEC1: alveolar type I cell; inh: inhibitor.