Immunology. 2024 Jan 4. doi: 10.1111/imm.13748. Online ahead of print.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disorder involving scarring of pulmonary tissue and a subsequent decrease in respiratory capacity, ultimately resulting in death. Tartrate resistant acid phosphatase 5 (ACP5) plays a role in IPF but the exact mechanisms are yet to be elucidated. In this study, we have utilized various perturbations of the bleomycin mouse model of IPF including genetic knockout, RANKL inhibition, and macrophage adoptive transfer to further understand ACP5's role in pulmonary fibrosis. Genetic ablation of Acp5 decreased immune cell recruitment to the lungs and reduced the levels of hydroxyproline (reflecting extracellular matrix-production) as well as histological damage. Additionally, gene expression profiling of murine lung tissue revealed downregulation of genes including Ccl13, Mmp13, and Il-1α that encodes proteins specifically related to immune cell recruitment and macrophage/fibroblast interactions. Furthermore, antibody-based neutralization of RANKL, an important inducer of Acp5 expression, reduced immune cell recruitment but did not decrease fibrotic lung development. Adoptive transfer of Acp5-/- bone marrow-derived monocyte (BMDM) macrophages 7 or 14 days after bleomycin administration resulted in reductions of cytokine production and decreased levels of lung damage, compared to adoptive transfer of WT control macrophages. Taken together, the data presented in this study suggest that macrophage derived ACP5 plays an important role in development of pulmonary fibrosis and could present a tractable target for therapeutic intervention in IPF.

PMID:38178705 | DOI:10.1111/imm.13748

Respir Res. 2024 Jan 4;25(1):5. doi: 10.1186/s12931-023-02588-y.

ABSTRACT

BACKGROUND: Interstitial lung diseases (ILD) comprise a heterogeneous group of mainly chronic lung diseases with more than 200 entities and relevant differences in disease course and prognosis. Little data is available on hospitalisation patterns in ILD.

METHODS: The EXCITING-ILD (Exploring Clinical and Epidemiological Characteristics of Interstitial Lung Diseases) registry was analysed for hospitalisations. Reasons for hospitalisation were classified as all cause, ILD-related and respiratory hospitalisations, and patients were analysed for frequency of hospitalisations, time to first non-elective hospitalisation, mortality and progression-free survival. Additionally, the risk for hospitalisation according to GAP index and ILD subtype was calculated by Cox proportional-hazard models as well as influencing factors on prediction of hospitalisation by logistic regression with forward selection.

RESULTS: In total, 601 patients were included. 1210 hospitalisations were recorded during the 6 months prior to registry inclusion until the last study visit. 800 (66.1%) were ILD-related, 59.3% of admissions were registered in the first year after inclusion. Mortality was associated with all cause, ILD-related and respiratory-related hospitalisation. Risk factors for hospitalisation were advanced disease (GAP Index stages II and III) and CTD (connective tissue disease)-ILDs. All cause hospitalisations were associated with pulmonary hypertension (OR 2.53, p = 0.005). ILD-related hospitalisations were associated with unclassifiable ILD and concomitant emphysema (OR = 2.133, p = 0.001) as well as with other granulomatous ILDs and a positive smoking status (OR = 3.082, p = 0.005).

CONCLUSION: Our results represent a crucial contribution in understanding predisposing factors for hospitalisation in ILD and its major impact on mortality. Further studies to characterize the most vulnerable patient group as well as approaches to prevent hospitalisations are warranted.

PMID:38178212 | PMC:PMC10765927 | DOI:10.1186/s12931-023-02588-y

Eur Respir J. 2024 Jan 4;63(1):2301954. doi: 10.1183/13993003.01954-2023. Print 2024 Jan.

NO ABSTRACT

PMID:38176704 | DOI:10.1183/13993003.01954-2023

Respir Med. 2024 Jan 2:107526. doi: 10.1016/j.rmed.2023.107526. Online ahead of print.

ABSTRACT

Patients with idiopathic fibrosing interstitial pneumonias (f-IIPs) mainly suffer from dyspnea. Refractory dyspnea, defined as persistent dyspnea despite optimal treatment, could be the signal to prescribe dyspnea relievers. We aimed to examine the prevalence and characteristics of refractory dyspnea in consecutive patients with f-IIPs. Refractory dyspnea was defined by an mMRC≥3 and also by a VAS dyspnea score≥2 at rest; the sensory and affective characteristics of refractory dyspnea (mMRC≥3) and associated quality of life (QoL) anxiety and depression were compared with non-refractory dyspnea (mMRC1-2) using the Multidimensional Dyspnea Profile (MDP), King's Brief Interstitial Lung Disease (KBILD) and Hospital Anxiety and Depression scale (HADs). We included 40 patients (24 men), aged 72 [68-79], FVC of 71 % [59-86] and DLCO 47 % [40-49]. Refractory dyspnea, was found in 38 % (95%CI:23-54) when defined by mMRC≥3 and in 67 % (95%CI:50-81) using a resting VAS dyspnea score ≥2. The agreement between the two definitions was low. Patients with refractory dyspnea (mMRC≥3) were more often women (60 % vs.28 %,p = 0.046), had a lower DLCO (24 % [22-43] vs.47 % [43-51],p = 0.014) and more frequently used oxygen (60 % vs.12 %,p = 0.003); they experience more intense air hunger (5/10 [(Johnson et al., 2017; Raghu et al., 2022; Banzett et al., 2015; Patel et al., 2012) 3-63-6 vs.2/10 [0-5],p = 0.018)). No significant differences were observed in VAS, MDP, KBILD, or HADs scores between refractory and non-refractory dyspnea patients. Our results indicate a significant frequency of refractory dyspnea in patients with f-IIPs and an association with air hunger but no impact on the affective dimension of dyspnea, anxiety, depression and QoL, suggesting that the mMRC score might not accurately identify patients distressed by their breathlessness.

PMID:38176572 | DOI:10.1016/j.rmed.2023.107526

BMC Pulm Med. 2024 Jan 5;24(1):15. doi: 10.1186/s12890-023-02831-8.

ABSTRACT

BACKGROUND: IPF is a complex lung disease whose aetiology is not fully understood, but diet may have an impact on its development and progression. Therefore, we investigated the potential causal connection between dietary intake and IPF through TSMR to offer insights for early disease prevention recommendations.

METHODS: The study incorporated 29 dietary exposure factors, oily fish intake, bacon intake, processed meat intake, poultry intake, beef intake, pork intake, lamb/mutton intake, non-oily fish intake, fresh fruit intake, cooked vegetable intake, baked bean intake, fresh tomato intake, tinned tomato intake, salad/raw vegetable intake, Fresh fruit intake, coffee intake, tea intake, water intake, red wine intake, average weekly beer plus cider intake, alcoholic drinks per week, cereal intake, bread intake, whole-wheat intake, whole-wheat cereal intake, cheese intake, yogurt intake, salt added to food and whole egg intake. The study explored the causal link between diet and IPF using TSMR analysis, predominantly the IVW method, and performed sensitivity analyses to validate the results.

RESULT: The study revealed that consuming oily fish, yogurt, and dried fruits had a protective effect against IPF, whereas the consumption of alcoholic beverages and beef was linked to an increased risk of IPF.

CONCLUSION: In this MR study, it was discovered that the consumption of oily fish, yogurt, and dried fruits exhibited a protective effect against IPF, whereas the intake of alcoholic beverages and beef was associated with an elevated risk of IPF. These findings underscore the significance of making informed and timely dietary decisions in IPF prevention.

PMID:38178024 | DOI:10.1186/s12890-023-02831-8

EMBO J. 2024 Jan;43(1):61-86. doi: 10.1038/s44318-023-00003-2. Epub 2023 Dec 15.

ABSTRACT

Accumulation of DNA damage in the lung induces cellular senescence and promotes age-related diseases such as idiopathic pulmonary fibrosis (IPF). Hence, understanding the mechanistic regulation of DNA damage repair is important for anti-aging therapies and disease control. Here, we identified an m6A-independent role of the RNA-binding protein YTHDC1 in counteracting stress-induced pulmonary senescence and fibrosis. YTHDC1 is primarily expressed in pulmonary alveolar epithelial type 2 (AECII) cells and its AECII expression is significantly decreased in AECIIs during fibrosis. Exogenous overexpression of YTHDC1 alleviates pulmonary senescence and fibrosis independent of its m6A-binding ability, while YTHDC1 deletion enhances disease progression in mice. Mechanistically, YTHDC1 promotes the interaction between TopBP1 and MRE11, thereby activating ATR and facilitating DNA damage repair. These findings reveal a noncanonical function of YTHDC1 in delaying cellular senescence, and suggest that enhancing YTHDC1 expression in the lung could be an effective treatment strategy for pulmonary fibrosis.

PMID:38177310 | DOI:10.1038/s44318-023-00003-2

Am J Respir Crit Care Med. 2024 Jan 4. doi: 10.1164/rccm.202312-2213SO. Online ahead of print.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) carries significant mortality and unpredictable progression, with limited therapeutic options. Designing trials with patient-meaningful endpoints, enhancing the reliability and interpretability of results, and streamlining the regulatory approval process are of critical importance to advancing clinical care in IPF.

METHODS: A landmark in-person symposium in June 2023 assembled 43 participants from the US and internationally, including patients with IPF, investigators, and regulatory representatives, to discuss the immediate future of IPF clinical trial endpoints. Patient advocates were central to discussions, which evaluated endpoints according to regulatory standards and the FDA's "feels, functions, survives" criteria.

RESULTS: Three themes emerged: 1) consensus on endpoints mirroring the lived experiences of patients with IPF; 2) consideration of replacing forced vital capacity (FVC) as the primary endpoint, potentially by composite endpoints that include 'feels, functions, survives' measures or FVC as components; 3) support for simplified, user-friendly patient-reported outcomes (PROs) as either components of primary composite endpoints or key secondary endpoints, supplemented by functional tests as secondary endpoints and novel biomarkers as supportive measures .

CONCLUSION: This report, detailing the proceedings of this pivotal symposium, suggests a potential turning point in designing future IPF clinical trials more attuned to outcomes meaningful to patients, and documents the collective agreement across multidisciplinary stakeholders on the importance of anchoring IPF trial endpoints on real patient experiences-namely, how they feel, function, and survive. There is considerable optimism that clinical care in IPF will progress through trials focused on patient-centric insights, ultimately guiding transformative treatment strategies to enhance patients' quality of life and survival.

PMID:38174955 | DOI:10.1164/rccm.202312-2213SO

Pulm Circ. 2024 Jan 3;14(1):e12311. doi: 10.1002/pul2.12311. eCollection 2024 Jan.

ABSTRACT

Pulmonary vascular dysfunction in the absence of pulmonary hypertension (PH) has been observed in patients with idiopathic pulmonary fibrosis (IPF). We describe the prevalence and etiology of elevated pulmonary vascular resistance (PVR) without PH among patients with IPF. Hemodynamic, echocardiographic, and functional respiratory imaging (FRI) data was compared between patients with IPF without PH with normal (<3 wood units) and elevated PVR (≥3 wood units). Mortality between these two groups were compared to patients with IPF and PH. Of 205 patients with IPF, there were 146 patients without PH, of whom 114 (78.1%) had a normal PVR and 32 (21.9%) who had a high PVR. Functional testing and hemodynamics were similar in the two groups, except for the cardiac index which was significantly lower in patients with a high PVR (2.3 vs. 2.6 L/min/m2; p = 0.004). Echocardiographic comparison demonstrated a higher tricuspid regurgitant velocity in those with a high PVR (3.4 vs 3.0 m/s; p = 0.046). FRI revealed proportionately fewer large vessels as a proportion of the vasculature in the patients without PH and elevated PVRs. Among patients without PH, PVR was associated with increased mortality. In conclusion, patients with IPF without PH but a high PVR appear to be a distinct phenotype with a prognosis between those with and without PH, likely reflecting the continuum of vascular dysfunction. The basis for this unique hemodynamic profile could not be definitively discerned although FRI suggested an aberrant anatomical vascular response.

PMID:38174158 | PMC:PMC10762875 | DOI:10.1002/pul2.12311

Respirol Case Rep. 2024 Jan 3;12(1):e01271. doi: 10.1002/rcr2.1271. eCollection 2024 Jan.

ABSTRACT

Extrapleural air is a rare condition that may concurrently develop with pneumomediastinum and pneumothorax, especially in older patients with fragile connective tissues. Physicians should consider extrapleural air to prevent inadvertent harm. Coronal reconstruction computed tomography images help appreciate extrapleural air and recognize the track of extrapulmonary air.

PMID:38173867 | PMC:PMC10763515 | DOI:10.1002/rcr2.1271

Heliyon. 2023 Dec 11;10(1):e23543. doi: 10.1016/j.heliyon.2023.e23543. eCollection 2024 Jan 15.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a chronic interstitial disease that cannot be cured, and treatment options for IPF are very limited. Early diagnosis, close monitoring of disease progression, and timely treatment are therefore the best options for patients due to the irreversibility of IPF. Effective markers help doctors judge the development and prognosis of disease. Recent research on traditional biomarkers (KL-6, SP-D, MMP-7, TIMPs, CCL18) has provided novel ideas for predicting disease progression and prognosis. Some emerging biomarkers (HE4, GDF15, PRDX4, inflammatory cells, G-CSF) also provide more possibilities for disease prediction. In addition to markers in serum and bronchoalveolar lavage fluid (BALF), some improvements related to the GAP model and chest HRCT also show good predictive ability for disease prognosis.

PMID:38173501 | PMC:PMC10761784 | DOI:10.1016/j.heliyon.2023.e23543

Diabetes Metab J. 2024 Jan 3. doi: 10.4093/dmj.2022.0367. Online ahead of print.

ABSTRACT

BACKGROUND: Nonalcoholic steatohepatitis (NASH) is a liver disease caused by obesity that leads to hepatic lipoapoptosis, resulting in fibrosis and cirrhosis. However, the mechanism underlying NASH is largely unknown, and there is currently no effective therapeutic agent against it. DWN12088, an agent used for treating idiopathic pulmonary fibrosis, is a selective prolyl-tRNA synthetase (PRS) inhibitor that suppresses the synthesis of collagen. However, the mechanism underlying the hepatoprotective effect of DWN12088 is not clear. Therefore, we investigated the role of DWN12088 in NASH progression.

METHODS: Mice were fed a chow diet or methionine-choline deficient (MCD)-diet, which was administered with DWN12088 or saline by oral gavage for 6 weeks. The effects of DWN12088 on NASH were evaluated by pathophysiological examinations, such as real-time quantitative reverse transcription polymerase chain reaction, immunoblotting, biochemical analysis, and immunohistochemistry. Molecular and cellular mechanisms of hepatic injury were assessed by in vitro cell culture.

RESULTS: DWN12088 attenuated palmitic acid (PA)-induced lipid accumulation and lipoapoptosis by downregulating the Rho-kinase (ROCK)/AMP-activated protein kinase (AMPK)/sterol regulatory element-binding protein-1c (SREBP-1c) and protein kinase R-like endoplasmic reticulum kinase (PERK)/α subunit of eukaryotic initiation factor 2 (eIF2α)/activating transcription factor 4 (ATF4)/C/EBP-homologous protein (CHOP) signaling cascades. PA increased but DWN12088 inhibited the phosphorylation of nuclear factor-κB (NF-κB) p65 (Ser536, Ser276) and the expression of proinflammatory genes. Moreover, the DWN12088 inhibited transforming growth factor β (TGFβ)-induced pro-fibrotic gene expression by suppressing TGFβ receptor 1 (TGFβR1)/Smad2/3 and TGFβR1/glutamyl-prolyl-tRNA synthetase (EPRS)/signal transducer and activator of transcription 6 (STAT6) axis signaling. In the case of MCD-diet-induced NASH, DWN12088 reduced hepatic steatosis, inflammation, and lipoapoptosis and prevented the progression of fibrosis.

CONCLUSION: Our findings provide new insights about DWN12088, namely that it plays an important role in the overall improvement of NASH. Hence, DWN12088 shows great potential to be developed as a new integrated therapeutic agent for NASH.

PMID:38173372 | DOI:10.4093/dmj.2022.0367

Eur Heart J Cardiovasc Imaging. 2024 Jan 3:jeae001. doi: 10.1093/ehjci/jeae001. Online ahead of print.

ABSTRACT

BACKGROUND: Systemic sclerosis (SSc) is characterized by vasculopathy, inflammation and fibrosis, and carries one of the worst prognoses if patients also develop pulmonary arterial hypertension (PAH). Although PAH is a known prognosticator, SSc-PAH patients demonstrate disproportionately high mortality, presumably due to cardiac involvement. In this cross-sectional study, the relation between cardiac involvement revealed by cardiovascular magnetic resonance (CMR) and systemic microvascular disease severity measured with nailfold capillaromicroscopy in SSc-PAH patients is evaluated, and compared to idiopathic PAH (IPAH) patients.

METHODS: SSc-PAH and IPAH patients underwent CMR, echocardiography, and nailfold capillaromicroscopy with post-occlusive reactivity hyperaemia (PORH)-testing on the same day. CMR imaging included T2- (oedema), native and postcontrast T1-mapping to measure the extracellular volume fraction (ECV, fibrosis), and adenosine-stress perfusion imaging measuring the relative myocardial upslope (microvascular coronary perfusion). Measures of peripheral microvascular function were related to CMR indices of oedema, fibrosis and myocardial perfusion.

RESULTS: SSc-PAH patients (n=20) had higher T2, and a trend towards a higher ECV, compared to IPAH patients (n=5), and lower nailfold capillary density (NCD) and reduced capillary recruitment after PORH. NCD correlated with ECV, and T2 (r=-0.443, and -0.464, respectively, p<0.05 for all), and with markers of diastolic dysfunction on echocardiography. PORH-testing, but not NCD, correlated with the relative myocardial upslope (r=0.421, p<0.05).

CONCLUSIONS: SSc-PAH patients showed higher markers of cardiac fibrosis and inflammation, compared to IPAH patients. These markers correlated well with peripheral microvascular dysfunction, suggesting that SSc-driven inflammation and vasculopathy concurrently affect peripheral microcirculation and the heart. This may contribute to the disproportionate high mortality in SSc-PAH.

PMID:38170546 | DOI:10.1093/ehjci/jeae001

Sci Rep. 2024 Jan 2;14(1):240. doi: 10.1038/s41598-023-50618-y.

ABSTRACT

Idiopathic Pulmonary Fibrosis (IPF) is a devastating form of respiratory disease with a life expectancy of 3-4 years. Inflammation, epithelial injury and myofibroblast proliferation have been implicated in disease initiation and, recently, epithelial-fibroblastic crosstalk has been identified as a central driver. However, the ability to interrogate this crosstalk is limited due to the absence of in vitro models that mimic physiological conditions. To investigate IPF dysregulated cross-talk, primary normal human bronchial epithelial (NHBE) cells and primary normal human lung fibroblasts (NHLF) or diseased human lung fibroblasts (DHLF) from IPF patients, were co-cultured in direct contact at the air-liquid interface (ALI). Intercellular crosstalk was assessed by comparing cellular phenotypes of co-cultures to respective monocultures, through optical, biomolecular and electrical methods. A co-culture-dependent decrease in epithelium thickness, basal cell mRNA (P63, KRT5) and an increase in transepithelial electrical resistance (TEER) was observed. This effect was significantly enhanced in DHLF co-cultures and lead to the induction of epithelial to mesenchymal transition (EMT) and increased mRNA expression of TGFβ-2, ZO-1 and DN12. When stimulated with exogenous TGFβ, NHBE and NHLF monocultures showed a significant upregulation of EMT (COL1A1, FN1, VIM, ASMA) and senescence (P21) markers, respectively. In contrast, direct NHLF/NHBE co-culture indicated a protective role of epithelial-fibroblastic cross-talk against TGFβ-induced EMT, fibroblast-to-myofibroblast transition (FMT) and inflammatory cytokine release (IL-6, IL-8, IL-13, IL-1β, TNF-α). DHLF co-cultures showed no significant phenotypic transition upon stimulation, likely due to the constitutively high expression of TGFβ isoforms prior to any exogenous stimulation. The model developed provides an alternative method to generate IPF-related bronchial epithelial phenotypes in vitro, through the direct co-culture of human lung fibroblasts with NHBEs. These findings highlight the importance of fibroblast TGFβ signaling in EMT but that monocultures give rise to differential responses compared to co-cultures, when exposed to this pro-inflammatory stimulus. This holds implications for any translation conclusions drawn from monoculture studies and is an important step in development of more biomimetic models of IPF. In summary, we believe this in vitro system to study fibroblast-epithelial crosstalk, within the context of IPF, provides a platform which will aid in the identification and validation of novel targets.

PMID:38168149 | DOI:10.1038/s41598-023-50618-y

BMC Pulm Med. 2024 Jan 2;24(1):10. doi: 10.1186/s12890-023-02776-y.

ABSTRACT

BACKGROUND: Idiopathic pulmonary fibrosis (IPF) is a progressive disease with a poor prognosis. Pulmonary function tests (PFTs) aid in evaluating the disease status of IPF. The clinical significance of oscillometry measurements in interstitial lung diseases has recently been reported. Our previous study showed that respiratory reactance (Xrs) measured by oscillometry reflected disease severity and predicted subsequent lung capacity decline in patients with IPF. However, the direct impact of Xrs on survival needs to be determined, and there are currently no reference values in oscillometry to predict prognosis. Therefore, this study aimed to investigate the association between oscillometry measurements, particularly Xrs, and survival in patients with IPF and to determine the cutoff values of Xrs that predict 3-year survival.

METHODS: We analyzed the relationship between the measured values of PFT and oscillometry derived from 178 patients with IPF. Univariate and multivariate Cox proportional hazards analyses were performed to investigate the relationships between clinical indices at the time of the first oscillometry and survival. We performed the time-dependent receiver operating characteristic (ROC) curve analysis to set the optimized cutoff values of Xrs for 3-year survival prediction. We examined the discriminating power of cutoff values of Xrs on survival using the Kaplan-Meier method and the log-rank test.

RESULTS: Xrs components, especially in the inspiratory phase (In), significantly correlated with the PFT values. In the multivariate analyses, Xrs (all of reactance at 5 Hz [X5], resonant frequency [Fres], and low-frequency reactance area [ALX] in the inspiratory phase) had a significant impact on survival (X5, p = 0.003; Fres, p = 0.016; ALX, p = 0.003) independent of age, sex, and other prognostic factors derived from the univariate analysis. The area under the ROC curve was 0.765, 0.759, and 0.766 for X5 In, Fres In, and ALX In, with cutoff values determined at - 0.98, 10.67, and 5.32, respectively. We found significant differences in survival after dividing patients using each of the cutoff values of Xrs.

CONCLUSIONS: In patients with IPF, Xrs measured by oscillometry significantly impacted survival. We also determined the cutoff values of Xrs to discriminate patients with poor prognoses.

PMID:38167026 | DOI:10.1186/s12890-023-02776-y

J Nanobiotechnology. 2024 Jan 3;22(1):14. doi: 10.1186/s12951-023-02251-0.

ABSTRACT

Idiopathic pulmonary fibrosis (IPF) is a highly debilitating and fatal chronic lung disease that is difficult to cure clinically. IPF is characterized by a gradual decline in lung function, which leads to respiratory failure and severely affects patient quality of life and survival. Oxidative stress and chronic inflammation are believed to be important pathological mechanisms underlying the onset and progression of IPF, and the vicious cycle of NOX4-derived ROS, NLRP3 inflammasome activation, and p38 MAPK in pulmonary fibrogenesis explains the ineffectiveness of single-target or single-drug interventions. In this study, we combined astragaloside IV (AS-IV) and ligustrazine (LIG) based on the fundamental theory of traditional Chinese medicine (TCM) of "tonifying qi and activating blood" and loaded these drugs onto nanoparticles (AS_LIG@PPGC NPs) that were inhalable and could penetrate the mucosal barrier. Our results suggested that inhalation of AS_LIG@PPGC NPs significantly improved bleomycin-induced lung injury and fibrosis by regulating the NOX4-ROS-p38 MAPK and NOX4-NLRP3 pathways to treat and prevent IPF. This study not only demonstrated the superiority, feasibility, and safety of inhalation therapy for IPF intervention but also confirmed that breaking the vicious cycle of ROS and the NLRP3 inflammasome is a promising strategy for the successful treatment of IPF. Moreover, this successful nanoplatform is a good example of the integration of TCM and modern medicine.

PMID:38166847 | DOI:10.1186/s12951-023-02251-0

2024 Oct 6. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

ABSTRACT

The diffusing capacity of the lungs for carbon monoxide (DLCO), also known as the transfer factor for carbon monoxide (TLCO), measures the amount of carbon monoxide (CO) transferred per minute from alveolar gas to red blood cells (RBCs). This test provides critical insights into the lungs' ability to transfer oxygen from inhaled air to the bloodstream, making it essential for diagnosing and monitoring various pulmonary conditions. Expressed in mL/min/mm Hg or mmol/min/kPa, the DLCO represents the volume of CO (in mL) transferred per minute for each unit of pressure difference (in mm Hg) across the total available functioning gas exchange surface in the lungs.

Clinicians use inhaled CO for this test because of its strong affinity for hemoglobin (Hgb). Oxygen is not preferred due to its weaker interaction with Hgb. Cardiac output and overall body consumption also limit oxygen uptake. Due to CO's strong binding to Hgb, this gas' absorption is primarily limited by changes to the alveolar-capillary membrane rather than blood flow, enabling clinicians to evaluate the membrane's integrity.

The DLCO helps evaluate patients with dyspnea, hypoxemia, emphysema, and interstitial lung disease (ILD) and serves as an early indicator for conditions like idiopathic pulmonary fibrosis (IPF) before spirometric changes are detectable. Additionally, DLCO determination helps clinicians monitor disease progression and therapy response and predict mortality. Any condition that reduces oxygen uptake will produce a similar decrease in CO uptake. Overlooking a low DLCO may be a missed opportunity for early intervention.

The Fick equation for gas diffusion helps explain the physiologic factors that affect the DLCO. The respiratory membrane forms the diffusing barrier and separates air within the alveoli from blood flowing in the pulmonary capillaries. The membrane consists of the alveolar epithelium, interstitium, and capillary endothelium. The DLCO results from 2 main measurements: alveolar volume accessible during a 10-second breath hold (Va) and the rate of alveolar capillary blood CO uptake (Kco).

The Fick equation is:

Vg=[k*(A)(ΔP)] / T ,

where V is the volume of gas transferred per unit of time, K is the diffusion coefficient of the gas, A is the surface area for gas exchange, ΔP is the partial pressure difference of gas, and T is the membrane thickness. The Fick equation demonstrates that factors that influence the movement of gas molecules across the capillary membrane include the membrane's surface area and thickness, as well as the driving pressure or pressure gradient across the capillary membrane.

Alterations in respiratory membrane properties, Hgb levels, and capillary blood volume contribute to DLCO variations. Gas diffusion across the alveolar membrane increases when the membrane surface area, alveolar pressure gradient, or gas solubility increases or when the membrane becomes thinner. Conversely, membrane thickening or a decrease in the membrane surface area, alveolar pressure gradient, or gas solubility reduces gas diffusion across the alveolar membrane.

Blood in the airways can also bind CO, and the DLCO may rise in the presence of hemoptysis and pulmonary hemorrhage. In contrast, anemia can decrease the DLCO. Measuring the DLCO is relatively simple and carries minimal risk, yet it provides critical insights into lung function, facilitating early detection and management of abnormalities. Incorporating DLCO testing into routine pulmonary evaluations can significantly improve patient outcomes and quality of care.

PMID:32310609 | Bookshelf:NBK556149

2024 Aug 17. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2024 Jan–.

ABSTRACT

Nintedanib is a small molecule tyrosine kinase inhibitor that binds to growth factor receptors, inhibiting the proliferation of fibroblasts. This action reduces ongoing fibrotic processes and delays the progression to long-lasting damage. Nintedanib is indicated for treating idiopathic pulmonary fibrosis, systemic sclerosis-associated interstitial lung disease, and progressive phenotype interstitial lung disease. This activity reviews the indications, contraindications, and adverse events associated with nintedanib therapy. The activity also covers the administration, pharmacokinetics, and relevant interactions of nintedanib, providing knowledge crucial for tailoring treatment to individual patient needs.

PMID:36251827 | Bookshelf:NBK585049

Heliyon. 2023 Dec 3;10(1):e23233. doi: 10.1016/j.heliyon.2023.e23233. eCollection 2024 Jan 15.

ABSTRACT

Long noncoding RNAs (lncRNAs) play a critical role in idiopathic pulmonary fibrosis (IPF); however, the underlying molecular mechanisms are unclear. Our study demonstrated that lncRNA small nucleolar RNA host gene 8 (SNHG8) was increased in bleomycin (BLM)-induced A549 cells. LncRNA SNHG8 overexpression further elevated fibrosis-related factors monocyte chemotactic protein 1 (MCP1), CC motif chemokine ligand 18 (CCL18), and α-smooth muscle actin (α-SMA), as well as increased collagen type I alpha-1 chain (COL1A1) and collagen type III alpha-1 chain (COL3A1). Meanwhile, lncRNA SNHG8 knockdown exhibited an opposite role in reducing BLM-induced pulmonary fibrosis. With regard to the mechanism, SNHG8 was then revealed to act as a competing endogenous RNA (ceRNA) for microRNA (miR)-4701-5p in regulating Mucin 5B (MUC5B) expression. Furthermore, the interactions between SNHG8 and miR-4701-5p, between miR-4701-5p and MUC5B, and between SNHG8 and MUC5B on the influence of fibrosis-related indicators were confirmed, respectively. In addition, SNHG8 overexpression enhanced the levels of transforming growth factor (TGF)-β1 and phosphorylation Smad2/3 (p-Smad2/3), which was suppressed by SNHG8 knockdown in BLM-induced A549 cells. Moreover, miR-4701-5p inhibitor-induced elevation of TGF-β1 and p-Smad2/3 was significantly suppressed by SNHG8 knockdown. In conclusion, SNHG8 knockdown attenuated pulmonary fibrosis progression by regulating miR-4701-5p/MUC5B axis, which might be associated with the modulation of TGF-β1/Smad2/3 signaling. These findings reveal that lncRNA SNHG8 may become a potential target for the treatment of IPF.

PMID:38163156 | PMC:PMC10756985 | DOI:10.1016/j.heliyon.2023.e23233

Mymensingh Med J. 2024 Jan;33(1):298-302.

ABSTRACT

We diagnosed and treated a case of Primary SjoGren's Syndrome with Idiopathic Pulmonary Fibrosis (IPF) in a 65 years old woman who presented with dyspnoea and multiple joint pains for 5 years and remained undiagnosed. She had variable presentation and was initially established as a case of mixed connective tissue disease which consists of Systemic Lupus Erythematosus (SLE), Systemic Sclerosis and Dermatomyositis. She complained of xerostomia, xerophthalmia, difficulty in opening mouth, progressive dysphagia with solid foods and raynaud's phenomenon. In addition to this she noticed photosensitive rash, oral ulcers and difficulty in raising arms above head especially while combing hair. Examination revealed bi basal fine end inspiratory crepitations unaltered while coughing, bed side 6 minutes walking test showed exertional desaturation of SpO2 from 92.0% to 84.0%. Grade 2 tenderness was noted in wrists, knees, elbows and small joints of hands and feet except DIP. However, no oral lesions or dental carries were found. Unstimulated salivary flow rate was 1.0 ml in 15 minutes and sublingual salivary pool was significantly reduced. Schirmer's test was positive. HRCT lung revealed reticulonodular shadowing, honey combing and traction bronchiectasis in basal segments of both lobes, suggestive of usual interstitial pneumonia in both lungs. Auto antibody tests revealed ANA, RA, anti CCP and anti ds DNA negative, CPK was 63U/L. ENA (Extractable Nuclear Antigen) profile demonstrated positive Anti SS- A antibody while it remained insignificant for anti SS-B, anti RNP, anti Sm antibody, anti Scl-7o, anti Jo-1. According to the American-European Consensus Criteria for SjoGren's Syndrome, it meets all the criteria to be diagnosed as Primary Sjogren's Syndrome. We finally diagnosed a case of Primary SjoGren's syndrome with IPF and the patient was treated with pirfenidone, prednisolone, artificial tears and vaccination against Haemophilus influenzae and Streptococcal pneumoniae. The 10 year survival rate for such patients is nearly 80.0%.

PMID:38163807

Arch Bronconeumol. 2023 Dec 18:S0300-2896(23)00403-9. doi: 10.1016/j.arbres.2023.12.002. Online ahead of print.

ABSTRACT

INTRODUCTION: Most patients with idiopathic pulmonary fibrosis (IPF) treated with antifibrotics (AF) have progressive disease despite treatment. A switch of AF may improve survival, but evidence from randomised controlled trials is missing. We aimed to evaluate the efficacy of an AF switch on survival and FVC decline in patients from the European MultiPartner IPF registry (EMPIRE).

METHODS: The study included 612 patients who discontinued the first antifibrotic therapy. Patients were grouped and analysed from two perspectives: (1) whether they had received a second antifibrotic treatment after the discontinuation of the first therapy, and (2) a reason for discontinuation of the first AF - "lack of efficacy" (LE) and "intolerance" (INT).

RESULTS: While 263 (43%) of 612 patients received no second AF ("non-switched"), 349 (57%) patients switched. Overall survival was higher in patients who received a second AF (median 50 vs. 29 months; adjusted HR 0.64, P=0.023). Similarly, the annual FVC decline was significantly reduced in switched patients: -98ml/y in switched and -172ml/y in non-switched patients (P=0.023), respectively. The switched patients had similar risk for mortality in both LE and INT groups (adjusted HR 0.95, P=0.85). The high impact of switching on survival was demonstrated in LE patients (adjusted HR 0.27, P<0.001).

CONCLUSION: The patients without a second AF had significantly shorter overall survival. Our analysis suggests the importance of switching patients with an ineffective first AF therapy to a second AF therapy.

PMID:38160169 | DOI:10.1016/j.arbres.2023.12.002