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Laryngotracheal stenosis (LTS) is a complex and heterogeneous disease whose pathogenesis remains unclear. LTS is considered to be the result of aberrant wound-healing process that leads to fibrotic scarring, originating from different aetiology. Although iatrogenic aetiology is the main cause of subglottic or tracheal stenosis, also autoimmune and infectious diseases may be involved in causing LTS. Furthermore, fibrotic obstruction in the anatomic region under the glottis can also be diagnosed without apparent aetiology after a comprehensive workup; in this case, the pathological process is called idiopathic subglottic stenosis (iSGS). So far, the laryngotracheal scar resulting from airway injury due to different diseases was considered as inert tissue requiring surgical removal to restore airway patency. However, this assumption has recently been revised by regarding the tracheal scarring process as a fibroinflammatory event due to immunological alteration, similar to other fibrotic diseases. Recent acquisitions suggest that different factors, such as growth factors, cytokines, altered fibroblast function and genetic susceptibility, can all interact in a complex way leading to aberrant and fibrotic wound healing after an insult that acts as a trigger. However, also physiological derangement due to LTS could play a role in promoting dysregulated response to laryngo-tracheal mucosal injury, through biomechanical stress and mechanotransduction activation. The aim of this narrative review is to present the state-of-the-art knowledge regarding molecular mechanisms, as well as mechanical and physio-pathological features behind LTS.

Idiopathic pulmonary fibrosis (IPF) is a fibrotic lung disease characterized by progressive loss of lung function and poor prognosis. The so-called acute exacerbation of IPF (AE-IPF) may lead to severe hypoxemia requiring mechanical ventilation in the intensive care unit (ICU). AE-IPF shares several pathophysiological features with acute respiratory distress syndrome (ARDS), a very severe condition commonly treated in this setting. A review of the literature has been conducted to underline similarities and differences in the management of patients with AE-IPF and ARDS. During AE-IPF, diffuse alveolar damage and massive loss of aeration occurs, similar to what is observed in patients with ARDS. Differently from ARDS, no studies have yet concluded on the optimal ventilatory strategy and management in AE-IPF patients admitted to the ICU. Notwithstanding, a protective ventilation strategy with low tidal volume and low driving pressure could be recommended similarly to ARDS. The beneficial effect of high levels of positive end-expiratory pressure and prone positioning has still to be elucidated in AE-IPF patients, as well as the precise role of other types of respiratory assistance (e.g., extracorporeal membrane oxygenation) or innovative therapies (e.g., polymyxin-B direct hemoperfusion). The use of systemic drugs such as steroids or immunosuppressive agents in AE-IPF is controversial and potentially associated with an increased risk of serious adverse reactions. Common pathophysiological abnormalities and similar clinical needs suggest translating to AE-IPF the lessons learned from the management of ARDS patients. Studies focused on specific therapeutic strategies during AE-IPF are warranted.

Aging and smoking are associated with the progressive development of three main pulmonary diseases: chronic obstructive pulmonary disease (COPD), interstitial lung abnormalities (ILAs), and idiopathic pulmonary fibrosis (IPF). All three manifest mainly after the age of 60 years, but with different natural histories and prevalence: COPD prevalence increases with age to >40%, ILA prevalence is 8%, and IPF, a rare disease, is 0.0005–0.002%. While COPD and ILAs may be associated with gradual progression and mortality, the natural history of IPF remains obscure, with a worse prognosis and life expectancy of 2–5 years from diagnosis. Acute exacerbations are significant events in both COPD and IPF, with a much worse prognosis in IPF. This perspective discusses the paradox of the striking pathological and pathophysiologic responses on the background of the same main risk factors, aging and smoking, suggesting two distinct pathophysiologic processes for COPD and ILAs on one side and IPF on the other side. Pathologically, COPD is characterized by small airways fibrosis and remodeling, with the destruction of the lung parenchyma. By contrast, IPF almost exclusively affects the lung parenchyma and interstitium. ILAs are a heterogenous group of diseases, a minority of which present with the alveolar and interstitial abnormalities of interstitial lung disease.

Interstitial lung diseases (ILDs) that are known as diffuse parenchymal lung diseases (DPLDs) lead to the damage of alveolar epithelium and lung parenchyma, culminating in inflammation and widespread fibrosis. ILDs that account for more than 200 different pathologies can be divided into two groups: ILDs that have a known cause and those where the cause is unknown, classified as idiopathic interstitial pneumonia (IIP). IIPs include idiopathic pulmonary fibrosis (IPF), non-specific interstitial pneumonia (NSIP), cryptogenic organizing pneumonia (COP) known also as bronchiolitis obliterans organizing pneumonia (BOOP), acute interstitial pneumonia (AIP), desquamative interstitial pneumonia (DIP), respiratory bronchiolitis-associated interstitial lung disease (RB-ILD), and lymphocytic interstitial pneumonia (LIP). In this review, our aim is to describe the pathogenic mechanisms that lead to the onset and progression of the different IIPs, starting from IPF as the most studied, in order to find both the common and standalone molecular and cellular key players among them. Finally, a deeper molecular and cellular characterization of different interstitial lung diseases without a known cause would contribute to giving a more accurate diagnosis to the patients, which would translate to a more effective treatment decision.

Background Ultrasound (US) evaluation of diaphragmatic dysfunction (DD) has proved to be a reliable technique in critical care. In this single-center prospective study, we investigated the impact of US-assessed DD on noninvasive ventilation (NIV) failure in patients with acute exacerbations of chronic obstructive pulmonary disease (AECOPD) and its correlation with the transdiaphragmatic pressure assessed using the invasive sniff maneuver (Pdi sniff). Methods A population of 75 consecutive patients with AECOPD with hypercapnic acidosis admitted to our respiratory intensive care unit (RICU) were enrolled. Change in diaphragm thickness (ΔTdi) < 20% during tidal volume was the predefined cutoff for identifying DD+/− status. Correlations between ΔTdi < 20% NIV failure and other clinical outcomes were investigated. Correlation between ΔTdi and Pdi sniff values was analyzed in a subset of ten patients. Results DD+ patients had a higher risk for NIV failure than DD− patients (risk ratio, 4.4; p  <  0.001), and this finding was significantly associated with higher RICU, in-hospital, and 90-day mortality rates; longer mechanical ventilation duration; higher tracheostomy rate; and longer RICU stay. Huge increases in NIV failure (HR, 6.2; p  < 0.0001) and 90-day mortality (HR, 4.7; p  = 0.008) in DD+ patients were found by Kaplan-Meier analysis. ΔTdi highly correlated with Pdi sniff (Pearson’s r  = 0.81; p  = 0.004). ΔTdi < 20% showed better accuracy in predicting NIV failure than baseline pH value and early change in both arterial blood pH and partial pressure of carbon dioxide following NIV start (AUCs 0.84 to DTdi < 20%, 0.51 to pH value at baseline, 0.56 to early change in arterial blood pH following NIV start, and 0.54 to early change in partical pressure of carbon dioxide following NIV start, respectively; p  < 0.0001). Conclusions Early and noninvasive US assessment of DD during severe AECOPD is reliable and accurate in identifying patients at major risk for NIV failure and worse prognosis.

Background Excessive inspiratory effort could translate into self-inflicted lung injury, thus worsening clinical outcomes of spontaneously breathing patients with acute respiratory failure (ARF). Although esophageal manometry is a reliable method to estimate the magnitude of inspiratory effort, procedural issues significantly limit its use in daily clinical practice. The aim of this study is to describe the correlation between esophageal pressure swings (Δ P es ) and nasal (Δ P nos ) as a potential measure of inspiratory effort in spontaneously breathing patients with de novo ARF. Methods From January 1, 2021, to September 1, 2021, 61 consecutive patients with ARF (83.6% related to COVID-19) admitted to the Respiratory Intensive Care Unit (RICU) of the University Hospital of Modena (Italy) and candidate to escalation of non-invasive respiratory support (NRS) were enrolled. Clinical features and tidal changes in esophageal and nasal pressure were recorded on admission and 24 h after starting NRS. Correlation between Δ P es and Δ P nos served as primary outcome. The effect of Δ P nos measurements on respiratory rate and Δ P es was also assessed. Results Δ P es and Δ P nos were strongly correlated at admission ( R 2  = 0.88, p  < 0.001) and 24 h apart ( R 2  = 0.94, p  < 0.001). The nasal plug insertion and the mouth closure required for Δ P nos measurement did not result in significant change of respiratory rate and Δ P es . The correlation between measures at 24 h remained significant even after splitting the study population according to the type of NRS (high-flow nasal cannulas [ R 2  = 0.79, p  < 0.001] or non-invasive ventilation [ R 2  = 0.95, p  < 0.001]). Conclusions In a cohort of patients with ARF, nasal pressure swings did not alter respiratory mechanics in the short term and were highly correlated with esophageal pressure swings during spontaneous tidal breathing. Δ P nos might warrant further investigation as a measure of inspiratory effort in patients with ARF. Trial registration : NCT03826797 . Registered October 2016.

Introduction The usual interstitial pneumonia (UIP) pattern, hallmark of idiopathic pulmonary fibrosis (IPF), may induce harmful local overdistension during mechanical ventilation given the juxtaposition of different tissue elasticities. Mechanotransduction, linking mechanical stress and strain to molecular pro-fibrotic pathways, likely contributes to fibrosis progression. Understanding the mechanical forces and aeration patterns in the lungs of IPF patients is crucial for unraveling potential mechanisms of disease progression. Quantitative lung computed tomography (CT) can accurately assess the air content of lung regions, thus informing on zonal distension. This study aims to investigate radiological evidence of lung over aeration in spontaneously breathing UIP patients compared to healthy controls during maximal inspiration. Methods Patients with IPF diagnosis referred to the Center for Rare Lung Diseases of the University Hospital of Modena (Italy) in the period 2020–2023 who underwent High Resolution Computed Tomography (HRCT) scans at residual volume (RV) and total lung capacity (TLC) using standardized protocols were retrospectively considered eligible. Patients with no signs of lung disease at HRCT performed with the same image acquisition protocol nor at pulmonary function test (PFTs) served as controls. Lung segmentation and quantitative analysis were performed using 3D Slicer software. Lung volumes were measured, and specific density thresholds defined over aerated and fibrotic regions. Comparison between over aerated lung at RV and TLC in the two groups and according to lung lobes was sought. Further, the correlation between aerated lung and the extent of fibrosis was assessed and compared at RV and TLC. Results IPF patients (N = 20) exhibited higher over aerated lung proportions than controls (N = 15) both at RV and TLC (4.5% vs. 0.7%, p < 0.0001 and 13.8% vs. 7%, p < 0.0001 respectively). Over aeration increased significantly from RV to TLC in both groups, with no intergroup difference (p = 0.67). Sensitivity analysis revealed significant variations in over aerated lung areas among lobes when passing from RV to TLC with no difference within lobes (p = 0.28). Correlation between over aeration and fibrosis extent was moderate at RV (r = 0.62, p < 0.0001) and weak at TLC (r = 0.27, p = 0.01), being the two significantly different at interpolation analysis (p < 0.0001). Conclusions This study provides the first evidence of radiological signs of lung over aeration in patients with UIP-pattern patients when passing from RV to TLC. These findings offer new insights into the complex interplay between mechanical forces, lung structure, and fibrosis and warrant larger and longitudinal investigations.

Patients with acute exacerbation of lung fibrosis with usual interstitial pneumonia (EUIP) pattern are at increased risk for ventilator-induced lung injury (VILI) and mortality when exposed to mechanical ventilation (MV). Yet, lack of a mechanical model describing UIP-lung deformation during MV represents a research gap. Aim of this study was to develop a constitutive mathematical model for UIP-lung deformation during lung protective MV based on the stress–strain behavior and the specific elastance of patients with EUIP as compared to that of acute respiratory distress syndrome (ARDS) and healthy lung. Partitioned lung and chest wall mechanics were assessed for patients with EUIP and primary ARDS (1:1 matched based on body mass index and PaO 2 /FiO 2 ratio) during a PEEP trial performed within 24 h from intubation. Patient’s stress–strain curve and the lung specific elastance were computed and compared with those of healthy lungs, derived from literature. Respiratory mechanics were used to fit a novel mathematical model of the lung describing mechanical-inflation-induced lung parenchyma deformation, differentiating the contributions of elastin and collagen, the main components of lung extracellular matrix. Five patients with EUIP and 5 matched with primary ARDS were included and analyzed. Global strain was not different at low PEEP between the groups. Overall specific elastance was significantly higher in EUIP as compared to ARDS (28.9 [22.8–33.2] cmH 2 O versus 11.4 [10.3–14.6] cmH 2 O, respectively). Compared to ARDS and healthy lung, the stress/strain curve of EUIP showed a steeper increase, crossing the VILI threshold stress risk for strain values greater than 0.55. The contribution of elastin was prevalent at lower strains, while the contribution of collagen was prevalent at large strains. The stress/strain curve for collagen showed an upward shift passing from ARDS and healthy lungs to EUIP lungs. During MV, patients with EUIP showed different respiratory mechanics, stress–strain curve and specific elastance as compared to ARDS patients and healthy subjects and may experience VILI even when protective MV is applied. According to our mathematical model of lung deformation during mechanical inflation, the elastic response of UIP-lung is peculiar and different from ARDS. Our data suggest that patients with EUIP experience VILI with ventilatory setting that are lung-protective for patients with ARDS.

Background Recent evidences show that Pulmonary Rehabilitation (PR) is effective in patients with Interstitial Lung Disease (ILD). It is still unclear whether disease severity and/or etiology might impact on the reported benefits. We designed this prospective study 1) to confirm the efficacy of rehabilitation in a population of patients with ILDs and 2) to investigate whether baseline exercise capacity, disease severity or ILD etiology might affect outcomes. Methods Forty-one patients (IPF 63%, age 66.9 ± 11 ys) were enrolled in a standard PR course in two centers. Lung function, incremental and endurance cyclo-ergometry, Six Minutes Walking Distance (6MWD), chronic dyspnea (Medical Research Council scale-MRC) and quality of life (St. George Respiratory Questionnaire-SGRQ) were recorded before and at the end of PR to measure any pre-to-post change. Correlation coefficients between the baseline level of Diffuse Lung Capacity for Carbon monoxide (DLCO), Forced Vital Capacity (FVC), 6MWD, power developed during incremental endurance test, GAP index (in IPF patients only) and etiology ( IPF or non-IPF ) with the functional improvement at the 6MWDT (meters), at the incremental and endurance cyclo-ergometry (endurance time) and the HRQoL were assessed. Results Out of the 41 patients, 97% ( n  = 40) completed the PR course. Exercise performance (both at peak load and submaximal effort), symptoms (iso-time dyspnea and leg fatigue), SGRQ and MRC significantly improved after PR ( p  < .001). Patients with lower baseline 6MWD showed greater improvement in 6MWD (Spearman r score = − .359, p  = .034) and symptoms relief at SGRQ ( r  = −.315, p  = .025) regardless of underlying disease. Conclusion Present study confirms that comprehensive rehabilitation is feasible and effective in patients with ILD of different severity and etiology. The baseline submaximal exercise capacity inversely correlates with both functional and symptom gains in this heterogeneous population.

Idiopathic pulmonary fibrosis (IPF) is one of the most aggressive forms of idiopathic interstitial pneumonias, characterized by chronic and progressive fibrosis subverting the lung’s architecture, pulmonary functional decline, progressive respiratory failure, and high mortality (median survival 3 years after diagnosis). Among the mechanisms associated with disease onset and progression, it has been hypothesized that IPF lungs might be affected either by a regenerative deficit of the alveolar epithelium or by a dysregulation of repair mechanisms in response to alveolar and vascular damage. This latter might be related to the progressive dysfunction and exhaustion of the resident stem cells together with a process of cellular and tissue senescence. The role of endogenous mesenchymal stromal/stem cells (MSCs) resident in the lung in the homeostasis of these mechanisms is still a matter of debate. Although endogenous MSCs may play a critical role in lung repair, they are also involved in cellular senescence and tissue ageing processes with loss of lung regenerative potential. In addition, MSCs have immunomodulatory properties and can secrete anti-fibrotic factors. Thus, MSCs obtained from other sources administered systemically or directly into the lung have been investigated for lung epithelial repair and have been explored as a potential therapy for the treatment of lung diseases including IPF. Given these multiple potential roles of MSCs, this review aims both at elucidating the role of resident lung MSCs in IPF pathogenesis and the role of administered MSCs from other sources for potential IPF therapies.