{'fraction_non_alphanumeric': 0.01868415821904194, 'fraction_numerical': 0.0021864440469091632, 'mean_word_length': 5.8, 'pattern_counts': {'":': 0, '<': 0, '<?xml version=': 0, '>': 0, 'https://': 0, 'lorem ipsum': 0, 'www.': 0, 'xml': 0}, 'pii_count': 0, 'substrings_counts': 0, 'word_list_counts': {'cursed_substrings.json': 0, 'profanity_word_list.json': 0, 'sexual_word_list.json': 0, 'zh_pornsignals.json': 0}}
The pulse of fibroblasts: circadian rhythm in pulmonary fibrosis development.

Life is rhythmic. From life phases down to minute molecular events in single cells. The principal external zeitgeber is light, which we sense and use to set the hypothalamic master circadian clock. Rhythms enable us to anticipate and adapt to the environment and thus survive; they persist for some time, even if external cues are removed. Seminal discoveries paved the way to elucidation of underlying molecular feedback loops in the last decades including work leading to a Nobel Prize in Physiology or Medicine in 2017. Some rhythms are easy to perceive such as day–night, eat–fast, endocrine/metabolic rhythms, or cardiac rhythm. These rhythms synchronize with each other and fine-tune by integrating organ-specific inputs. More recently, we began to understand that also organs or cells that we do not usually perceive as rhythmic exhibit inherent circadian rhythmicity. Work demonstrating oscillatory expression of not only core clock genes but the majority of protein-coding genes with distinct patterns and phases according to tissue type evidenced to which extent phasic regulation of molecular processes takes place. In the lung, circadian oscillations are present in epithelia and drive inflammatory responses. Cunningham et al. now demonstrate that circadian rhythms also apply to pulmonary fibroblast biology and extracellular matrix remodelling. In their article, the authors first show that circadian rhythm reporter mPER2 oscillations are amplified but asynchronous in fibrotic lung areas. They then demonstrate that knockdown of the core clock nuclear orphan receptor REVERBa in PDGFRb positive cells amplifies bleomycin-induced pulmonary fibrosis. This associates with suppression of the transcription factor TBPL1 and induction of integrinb1-positive focal adhesion complexes in activated fibroblasts. Disruption of integrinb1 expression abolished fibroblast activation suggesting that integrin-mediated mechano-transduction is necessary in this process. The authors further demonstrate that transforming growth factor beta (TGFb) (phase shift) or mechanosensing (amplitude) modify circadian oscillations (Figure 1). Lastly, they show that pulmonary fibrosis is more prevalent in shift workers in participants of the UK Biobank and that small molecule REVERBa agonism reduces TGFb-induced fibroblast activation in primary lung fibroblasts and tissue. Several findings are remarkable. First, extracellular matrix remodelling and fibrosis develop over extended time periods and are usually not perceived as classic circadian oscillatory phenomena. Second, the paper emphasizes that circadian clocks are finely tuned. This applies not only to synchronizing the central master clock in the hypothalamic suprachiasmic nuclei with organor cell-autonomous clocks but also the integration of classic fibrotic signalling such as TGFb and mechano-transduction (Figure 1). The requirement of integrin signalling supports the key role of mechanic tissue properties in fibrogenesis. Paratensile signalling between fibroblasts or location-dependent TGFb mechano-signalling in pulmonary fibrosis progression also evidence the role of mechanotransduction in fibrosis. Interestingly, mechanical cues may also directly tune organ-specific circadian clocks. What are the implications for the heart and potential therapeutic translation? The heart is similar to the lung in that both organs have their own incessant autonomous oscillations—heartbeat and breathing. Evidently, circadian rhythmicity substantially affects organ biology on top of theses autonomous oscillations. This includes extracellular matrix remodelling and fibrosis development and integrates paracrine signalling and mechanical cues. Interstitial fibrosis develops gradually and is a hallmark of ageing in many organs. It is thus intriguing to speculate that circadian clocks that are out of tune reciprocally influence fibrosis development during ageing given that circadian dysfunction aggravates age-related pathologies. In the heart, stress responses such as myocardial infarction occurrence and healing may differ according to time of the day, although books are not yet closed on its clinical significance. In a more controlled setting, REVERBa regulates circadian dependence of myocardial injury of elective on-pump aortic valve surgery. Contrary to pulmonary fibrosis development, REVERBa antagonism was beneficial in mouse heart Langendorff ischaemia-reperfusion injury in this study. In fact, REVERBa expression was paradoxically up in idiopathic pulmonary fibrosis lung tissue despite its apparent fibrosis-inhibiting properties, potentially due to adaptive feedback loops. In contrast, in cardiomyocytespecific BMAL1 knockout mice with dysregulated circadian clocks in the heart, REVERBa agonism normalized some measures of adverse cardiac remodelling including interstitial fibrosis; this would be in line with Cunningham and co-workers’ findings in pulmonary fibrosis.