Issue 2, Volume 3 – 5 articles

Open Access

Letter

07 April 2025
Open Access

Review

22 May 2025

NLRP3 Inflammasome and IL-11 in Systemic Sclerosis Pulmonary Fibroblasts

Systemic sclerosis (SSc) is an autoimmune disease characterized by widespread fibrosis affecting multiple organ systems. There is clinical heterogeneity among patients with SSc in terms of the organs affected. However, the pathophysiology of the disease remains elusive. The NLRP3 inflammasome is upregulated in SSc and exerts its fibrotic effects through activation of caspase-1, which in turn activates a fibrotic signaling cascade, resulting in increased collagen deposition and myofibroblast transition. Recently, IL-11 has been shown to be elevated in disease and has been shown to participate in downstream signaling via the NLRP3 inflammasome. A significant number of patients with SSc will develop pulmonary involvement, termed interstitial lung disease (SSc-ILD). Though this type of pulmonary involvement is distinct from other types of pulmonary fibrosis (such as idiopathic pulmonary fibrosis), it may be a valuable model to study mechanisms of fibrosis that could apply to other fibrotic diseases. Here, we discuss recent advances in understanding the mechanisms of the NLRP3 inflammasome and IL-11 in SSc pulmonary fibroblasts. We tie together some of the recent findings, such as senescence, the unfolded protein response, and reactive oxygen species, that contribute to fibrotic pathology via modulating NLRP3 activation, possibly leading to IL-11 expression.

Open Access

Article

25 June 2025

Time Is Lung: Inpatient Transbronchial Lung Cryobiopsy Decreases Wait Time to Treatment Initiation for Newly Diagnosed Interstitial Lung Disease

Although performing lung biopsies on hospitalized patients with interstitial lung disease (ILD) has risk, initial studies have shown transbronchial lung cryobiopsy (TBLC) may be safely performed in this patient group. Data evaluating the value of this intervention in establishing a diagnosis and impacting management is lacking. We present a comparison of TBLC for inpatients and outpatients and provide data on the impact on medical therapy initiation and wait times from consultation to biopsy and treatment. Demographic data, pulmonary function values, chest imaging patterns, procedural information, diagnosis, and medical therapy changes, defined as medication initiation, adjustment, or cessation guided by TBLC results, were recorded from enrolled patients with newly identified ILD. Changes in medical therapy were the primary outcome. Time from consultation to biopsy and treatment was the secondary outcome. Fifty-four (54) patients (40 outpatient, 14 inpatient) were included. Inpatients underwent biopsy 2.5 ± 4.4 days after consultation compared to 15.5 ± 16.1 days for outpatients (p < 0.001). Medical therapy changes occurred 10.3 ± 7.9 days after biopsy for inpatients compared to 34.6 ± 37.0 days for outpatients (p < 0.001). There were no significant differences in medical therapy changes between the groups (p = 0.45). Our initial study suggests that performing TBLC on inpatients with newly identified ILD decreases wait times to treatment initiation and diagnosis. Efforts to understand the impact of a decreased wait time on ILD prognosis, including the development of progressive disease or fibrosis, symptom evolution, and quality of life, require further evaluation.

Open Access

Review

27 June 2025

Targeting Collagen Secretion as a Potential Therapeutic Strategy to Modulate Fibrosis

Fibrotic diseases are driven by the excessive accumulation of extracellular matrix (ECM), particularly collagens, leading to progressive tissue stiffness and organ dysfunction. While many factors contribute to fibrosis—including cytokine signaling, integrin-mediated mechanotransduction, and altered ECM degradation—the synthesis and secretion of collagen remain central bottlenecks. Collagen biosynthesis is a complex process involving extensive post-translational modification and intracellular trafficking. The export of procollagen from the endoplasmic reticulum (ER) requires Transport and Golgi Organisation 1 (TANGO1), a transmembrane organizer of ER exit sites that coordinates cargo selection, membrane remodeling, and connectivity between the ER and the ER-Golgi-Intermediate-Comaprtment (ERGIC). By assembling into ring-like structures at ER exit sites, TANGO1 builds a secretory route for bulky cargoes that bypasses conventional vesicle constraints. Loss of TANGO1 disrupts collagen secretion and causes developmental defects across various species. In fibrotic tissues, TANGO1 expression is upregulated, linking secretory machinery to pathological matrix deposition. Recent work has identified specific interfaces within the complex of TANGO1 with its vertebrate paralogue Cutaneous T-cell lymphoma-associated antigen 5 (cTAGE5) as targets for cell-permeant peptide inhibitors. Inhibitors that selectively and specifically block TANGO1 complex formation reduce collagen secretion in fibroblasts and scar formation in vivo, offering a new strategy to modulate fibrotic processes.

Open Access

Review

27 June 2025

Fibroblast Migration in Fibrosis

Fibroblast migration is a critical factor in wound healing, but also plays a fundamental role in fibrosis. For a fibroblast to migrate, the cell must be able to assemble factors that help it crawl across the extracellular matrix. Most of this movement is facilitated through the assembly and stability of the cytoskeleton that connects focal adhesion engagement with the extracellular matrix to intracellular stress fibers that wrap around the nucleus. These intracellular stress fibers help to polarize the fibroblast and orient the nucleus in the direction it is traveling. Changes in intracellular signaling for the fibroblast to move are also required, and this is necessitated by downstream signaling mediated by sonic hedgehog, WNT/β-catenin, ROCK/Rho, and PI3K/AKT. These changes regulate the stability of the cytoskeleton and, in addition, increase the expression of genes involved in cell migration. This review assimilates what is known about the function of the cytoskeleton in migration and the role of intracellular signaling pathways in fibrosis.

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