This study reports a significant proportion of over aerated lung as assessed by quantitative CT analysis in spontaneously breathing IPF patients when passing from RV to TLC. Further, a significant relationship between over aeration and the extent of lung fibrosis was reported, independent on the different lung lobes.

To the best of our knowledge, this study presents the first evidence showing that patients with UIP pattern exhibit radiological signs of lung over aeration during the breathing transition from RV to TLC, similarly to what observed in healthy controls. Furthermore, the proportion of parenchyma experiencing over aeration within a maximal spontaneous inspiration is greater in patients with UIP pattern as compared to that observed in individuals with normal lung function. Moreover, in IPF, a proportion of lung parenchyma shows over aeration even during deflation, when RV level is reached.

For the first time, we here describe the dynamic behavior of the lung with UIP pattern, as based on the static morphometry, thus redefining the concept that describes pulmonary fibrosis as a disease only characterized by restriction of lung volumes with a homogeneous hypo-aeration during lung inflation. Lung fibrosis causes a progressive reduction in lung volumes as a whole, as described by standard functional tests. However, the heterogeneity of the UIP pattern can generate a peculiar mechanical response and air distribution when subjected to deformation, such as during inflation. Indeed, The UIP lung architecture, consists of a patchwork of tissues with varying elasticities. When pressure is applied, it results distributed unevenly: the rigid areas resist deformation, while the more elastic regions bear the mechanical stress [23]. We firstly hypothesized this phenomenon in IPF patients undergoing MV. In this setting, the external application of positive end-expiratory pressure can cause the more flexible lung areas to protrude through the surrounding stiff fibrotic tissue, leading to increased rigidity and potential tissue breakdown [10]. This effect resembles that of "squishy balls” and may explain some mechanical disadvantages during ventilation. In the present study, we showed that the UIP pattern can facilitate a zonal increase in air content that can no longer be described by a standard functional evaluation (i.e. spirometry). This observation of zonal over-aeration in lung parenchyma on CT scans supports our "squishy ball" hypothesis, and extends this concept to IPF patients even when breathing spontaneously.

The concept of “zonal over-aeration” in the fibrotic lung should not be misleading. Indeed, it should not be confused with the phenomenon of lung hyperinflation which is typical of other diseases such as chronic obstructive pulmonary disease (COPD). The “squishy ball” theory has clearly different physiological and biological implications. Pulmonary hyperinflation is usually defined as an abnormal increase of the gas volume in the lungs at the end of tidal expiration (i.e. functional residual capacity) in patients suffering from COPD [24]. In this case, both reduction of the lung elastic recoil pressure and the increase of the airway resistance lead to increased time for lung emptying. The physiological consequence of this so called dynamic hyperinflation is the progressive air trap in the lung under specific conditions such as exercise or disease exacerbation, which leads in turn to exertional dyspnea and may have deleterious effects on diaphragm and cardiovascular functions [25].

Despite some physiological studies have shown an increase of airflow resistance in the small airways also of patients with ILD, the development of dynamic hyperinflation does not occur [26]. In addition, a recent study by Chuang did not report any exercise-induced dynamic hyperinflation in ILD patients during physical exercise [1].

Although it seems reasonable to understand that the physiological consequences of the zonal parenchyma over aeration of the fibrotic lung are less likely to increase symptoms per se in patients with ILD and at difference with COPD [27], the biological consequences could be different. Indeed, the protrusion of lung areas with spared elasticity (i.e. the areas of parenchyma with over aeration as described in our study) could occur within the context of dense inelastic fibrotic tissue; hence, the onset of non-physiological stretches may activate intracellular mechanotransduction pathways, thus favoring the progression of local fibrosis [13]. It Is now well known that cells receive mechanical cues via mechanosensitive proteins at the cell membrane-cytoskeletal cortex interface, and un-physiological mechanical stimuli, through the activation of intracellular pathways, may transiently or persistently alter cellular programs that drive injury, repair, and fibrosis responses [3, 14].

The clinical observation that pulmonary fibrosis progresses along a mechanical stress gradient, supports the hypothesis that the elastic and mechanical behavior of the “squishy ball” model could be one of the key mechanisms of the abnormal activation of the mechanotransduction pathways, suggesting a link between non-physiological stretch and progression/extension of lung fibrosis. Particularly, we hypothesize that if the fibrotic UIP-lung reaches a certain extent of fibrosis it may undergo potentially hazardous deformations when subjected to significant volume changes (i.e. from RV to TLC). Such deformations could further activate unfavorable mechanotransduction pathways [14].

Therefore, this behavior might constitute a form of lung injury induced by the unfair interplay among areas of the lung having different elasticities, which we can so label as “stiff tissue induced lung injury”.

Finally, present data have also shown that in patients with UIP lung, there exists a portion of over aeration even at RV. We speculate that this finding might be related to the impact of fibrosis on terminal airways, thus promoting tele-expiratory collapse and air trapping when lung volume reaches its minimum during expiration. ILD patients can show either a preserved or elevated RV/TLC ratio, given the premature closure of small airways and gas trapping [28].

This study employs quantitative lung CT analysis to assess the abnormal proportion of over-aerated lung tissue during the spontaneous breathing transition from RV to TLC. The presence of over aeration even at RV suggests potential air trapping and tele-expiratory collapse in the fibrotic lung with UIP pattern, and challenges the traditional view of a uniform hypo-aeration during lung inflation in IPF. Moreover, the study's speculation on a possible "stiff tissue-induced lung injury" underscores the critical relevance of mechanical factors in the clinical progression of the disease.

Nevertheless, present investigation is burdened by several limitations. First, the single-center retrospective design and the limited sample may introduce bias and limit the ability to establish causation. The lack of a dynamic quantitative CT evaluation during spontaneous breathing further represents a major flaw.

Future prospective studies with larger and more diverse cohorts could validate and extend the current findings. Longitudinal assessments of change of lung mechanics in patients with IPF may provide insights into the evolution of zonal over-aeration in the lungs and, as such, its relationship to the progression of fibrosis.