特発性間質性肺炎

Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal interstitial lung disease characterized by usual interstitial pneumonia, relentless decline in lung function and incomplete disease modification by available antifibrotic therapies. Beyond canonical profibrotic pathways, accumulating evidence identifies aberrant glutamine metabolism as a convergent metabolic feature of IPF pathogenesis. In structural cells, glutaminolysis fuels myofibroblast activation, de novo glycine and proline synthesis for collagen, whereas epithelial glutamine utilization may support antioxidant defence, mitochondrial adaptation and repair. In immune cells, glutamine shapes macrophage and T-cell polarization and may contribute to an inflammatory, profibrotic microenvironment. Glutamine-derived intermediates intersect with mTOR/AMPK and TGF-β/Smad signalling and act as cofactors for epigenetic regulators, thereby stabilizing apoptosis-resistant, profibrotic transcriptional programmes. Experimental models and human studies further demonstrate upregulation of glutamine transporters and glutaminase 1 (GLS1) in fibrotic lungs, protection from bleomycin-induced fibrosis after genetic or pharmacologic GLS1 inhibition, and a genetic association between lower circulating glutamine and increased IPF risk. Importantly, the effects of glutamine metabolism are context- and cell type-dependent: epithelial and immune glutamine utilization may support repair, barrier integrity and host defence, whereas excessive fibroblast-directed glutaminolysis promotes matrix accumulation. Building on these observations, this review synthesizes current knowledge on cell type-relevant glutamine metabolism in lung fibrosis, distinguishes direct lung-fibrosis evidence from extrapolated mechanistic evidence, delineates its integration with fibrogenic signalling, oxidative stress, mitochondrial stress and immunometabolism, and critically evaluates the therapeutic potential and caveats of targeting glutamine uptake, catabolism and nutrient-sensing pathways as adjuncts to existing antifibrotic regimens.

INTRODUCTION: Combined Pulmonary Fibrosis and Emphysema (CPFE) is a syndrome characterized by the coexistence of emphysema and pulmonary fibrosis on High-Resolution Computed Tomography (HRCT), typically presenting with preserved lung volumes and markedly reduced diffusing capacity, and may occur in association with connective tissue diseases. A systematic review of the literature was conducted to improve understanding of its clinical profile and present two unusual cases linked to idiopathic inflammatory myopathies. METHODS: A systematic search of Medline, Embase, and Scopus was performed following PRISMA guidelines. Sixty articles were included, addressing diagnosis, pathophysiology, risk factors, prognosis, and treatment. A summary of reported cases was also compiled. RESULTS: An international consensus statement established a definition for clinical and research purposes, requiring emphysema to involve≥15% of the lung parenchyma. Reported risk factors include older age, male sex, smoking, mediastinal lymphadenopathy, fibrosis extent, high-titer rheumatoid factor, or anti-Ro/SSA antibodies. Prognostic determinants of mortality or progression include the extent of fibrosis, decline in DLCO, and pulmonary hypertension. Paraseptal emphysema and usual interstitial pneumonia are the most common radiologic findings. Twenty-seven studies reported patients, mainly associated with systemic sclerosis (19.7% in smokers, 7.5% in never-smokers) and rheumatoid arthritis, while only two cases were linked to myopathies. Management relies on immunosuppressive therapy directed at the underlying disease, with early initiation potentially modifying disease course. Additional measures include inhalation therapy, antifibrotic agents, pulmonary hypertension treatment, and rehabilitation. DISCUSSION: CPFE is an uncommon but clinically relevant complication with distinct risk and prognostic factors. Pulmonary hypertension is frequent. Cases associated with myopathies are rare. Immunosuppressive therapy remains central and may slow disease progression. CONCLUSION: CPFE is a distinct and clinically significant condition associated with increased morbidity and mortality, requiring accurate recognition and multidisciplinary management.

Pulmonary hypertension (PH) is a common complication of interstitial lung disease (ILD), yet data on screening in heterogenous ILD populations are limited. We evaluated whether routinely measured pulmonary function test (PFT) parameters identify individuals with intermediate-to-high echocardiographic risk of PH. 432 ILD patients met inclusion criteria with an echocardiogram reporting peak tricuspid regurgitant velocity (TRV) and a PFT reporting diffusion impairment (DLCO) within 1 year (median interval, 39 days). Of these, 126 underwent right heart catheterization (RHC). Age- and sex- adjusted logistic regression assessed associations between %predicted forced vital capacity (FVC), %predicted DLCO, and FVC/DLCO ratio with intermediate-to-high echocardiographic PH probability (TRV > 2.8 m/s). Receiver operating characteristic curves evaluated diagnostic performance. The cohort included 28% systemic autoimmune rheumatic disease-associated ILD, 27% interstitial pneumonia with autoimmune features, and 6% idiopathic pulmonary fibrosis, with a mean age of 72% and 54% female. Lower FVC and DLCO were associated with higher odds of echocardiographic PH (OR 1.35, 95%CI 1.21-1.50; OR 1.50, 95%CI 1.36-1.73) and increases in FVC/DLCO ratio similarly predicted risk (OR 1.83, 95%CI 1.44-2.32). DLCO had the highest predictive ability (AUC 0.74, 95%CI 0.69-0.79) with an optimal cut-off of 42% (sensitivity 67%, specificity 74%). In patients who underwent RHC, TRV > 2.8 m/s correlated with mean pulmonary artery pressure (r = 0.55, 95%CI 0.42-0.66) and tripled the odds of confirmed PH (OR 3.75, 95%CI 2.25-6.24). In sum, severe diffusion impairment, regardless of fibrosis extent, may detect patients with ILD who warrant echocardiographic screening, specialty PH referral, and consideration of RHC.

BACKGROUND: Lipid-laden macrophages (LLMs) have been shown to be associated with lung inflammation and fibrosis. However, the clinical significance of LLM in interstitial lung disease (ILD) remains unclear. We conducted a retrospective study with the aim of evaluating whether the LLM index in bronchoalveolar lavage fluid (BALF) is a reliable biomarker reflecting disease severity and responsiveness to steroid treatment in patients with ILD. METHODS: Patients who underwent bronchoscopy with Oil Red O staining for the evaluation of ILD between 2022 and 2023 were consecutively recruited. ILD was diagnosed based on chest computed tomography findings and clinical evaluation, in accordance with the official guidelines. LLM indices were calculated based on the staining intensity of macrophages in BALF. Disease severity was evaluated cross-sectionally based on baseline pulmonary function tests, and its correlation with the LLM index was assessed using Spearman's correlation analysis. Furthermore, in patients with ILD who received steroid treatment, the association between the LLM index and therapeutic response was retrospectively evaluated. RESULTS: Among 19 cases, the median age was 69 years, and 12 patients were male. Eleven cases had a history of smoking. ILD subtypes included hypersensitivity pneumonitis (n=5), collagen vascular disease-related interstitial pneumonia (n=4), interstitial pneumonia with autoimmune features (n=2), idiopathic pulmonary fibrosis (n=2), cryptogenic organizing pneumonia (n=2), nonspecific interstitial pneumonia (n=1), desquamative interstitial pneumonia (n=1), respiratory bronchiolitis-associated ILD (n=1), and drug-induced pneumonia (n=1). The LLM index was negatively correlated with the percentage of predicted forced vital capacity (ρ=-0.5638, P=0.02) and positively correlated with the neutrophil fraction in BALF (ρ=0.4938, P=0.03). Furthermore, among the 10 cases in which corticosteroids were administered after bronchoscopy, the LLM index was negatively correlated with the reduction in serum KL-6 level from baseline to 3 months after treatment (ρ=-0.7983, P<0.01). CONCLUSIONS: Although limited by the small sample size, heterogeneous populations, and the pilot nature of this study, our findings suggest that the LLM index in BALF may be associated with disease severity and short-term corticosteroid response in patients with ILD. These findings should be validated in prospective studies with larger sample sizes.

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive fibrosing interstitial lung disease with a poor prognosis. Honeycombing on high-resolution computed tomography (HRCT) is a defining feature of the usual interstitial pneumonia (UIP) pattern and has traditionally been considered a marker of advanced disease. However, in the era of antifibrotic treatment (AFT), the prognostic significance of the UIP pattern in IPF remains uncertain. This study aimed to evaluate the association between HRCT UIP pattern and long-term prognosis in patients with IPF receiving AFT. METHODS: This retrospective multicenter study investigated consecutive patients with IPF who initiated AFT between 2009 and 2019 at seven institutions in Japan. HRCT patterns were classified as UIP or non-UIP by multidisciplinary assessment. The primary outcome was IPF-related events, defined as IPF-related death or first acute exacerbation (AE) after initiating AFT. Event-free survival was analyzed using Kaplan-Meier methods with stratification by gender-age-physiology (GAP) stage. Propensity score matching (PSM) was performed to adjust for age, sex, GAP score, and antifibrotic agent. RESULTS: Of the 139 patients included, 99 had a UIP pattern, and 40 had a non-UIP pattern. In the overall cohort, event-free survival did not differ significantly. Stratified analyses showed no significant survival difference between UIP and non-UIP patterns among GAP Stage I patients (median survival time [MST]: 2050 vs. 1104 days; p = 0.90). Similarly, among patients with GAP Stages II-III, MST did not differ significantly. After PSM, 34 matched pairs were analyzed, and no significant differences in event-free survival were observed between UIP and non-UIP patterns. CONCLUSIONS: In patients with IPF treated with AFT, the radiological UIP pattern on HRCT was not independently associated with long-term prognosis. Multidimensional risk assessment incorporating physiological impairment and disease behavior may provide more accurate prognostic stratification in treated UIP populations.