From coffee beans flowing in a chute to cells remodelling in a living tissue, a wide variety of close-packed collective systems— both inert and living—have the potential to jam. The collective can sometimes flow like a fluid or jam and rigidify like a solid. The unjammed-to-jammed transition remains poorly understood, however, and structural properties characterizing these phases remain unknown. Using primary human bronchial epithelial cells, we show that the jamming transition in asthma is linked to cell shape, thus establishing in that system a structural criterion for cell jamming. Surprisingly, the collapse of critical scaling predicts a counter-intuitive relationship between jamming, cell shape and cell–cell adhesive stresses that is borne out by direct experimental observations. Cell shape thus provides a rigorous structural signature for classification and investigation of bronchial epithelial layer jamming in asthma, and potentially in any process in disease or development in which epithelial dynamics play a prominent role.

Obesity is associated with the development of asthma and considerable asthma-related healthcare utilization. To understand the immunological pathways that lead to obesity-associated asthma, we fed mice a high fat diet for 12 weeks, which resulted in obesity and the development of airway hyperreactivity (AHR), a cardinal feature of asthma. This AHR depended on innate immunity, since it occurred in obese Rag−/− mice, and on IL-17A and the NLRP3 inflammasome, since it did not develop in obese Il17−/− or Nlrp3−/− mice. The AHR was also associated with the presence in the lungs of CCR6+ innate lymphoid cells producing IL-17A (ILC3 cells), which could by themselves mediate AHR when adoptively transferred into Rag2−/− Il2rγ−/− mice. IL-1β played an important role by expanding the ILC3 cells, and treatment to block the function of IL-1β abolished obesity-induced AHR. Since we found ILC3-like cells in the bronchoalveolar lavage fluid of human patients with asthma, we suggest that obesity-associated asthma is facilitated by inflammation mediated by NLRP3, IL-1β and ILC3 cells.

In the classic theory of airway lumen narrowing in asthma, active force in airway smooth muscle is presumed to be in static mechanical equilibrium with the external load against which the muscle has shortened. This theory is useful because it identifies the static equilibrium length toward which activated airway smooth muscle would tend if given enough time. The corresponding state toward which myosin-actin interactions would tend is called the latch state. But are the concepts of a static mechanical equilibrium and the latch state applicable in the setting of tidal loading, as occurs during breathing? To address this question, we have studied isolated, maximally contracted bovine tracheal smooth muscle subjected to tidal stretches imposed at 0.33 Hz. We measured the active force (F) and stiffness (E), which reflect numbers of actin-myosin interactions, and hysteresivity (eta) which reflects the rate of turnover of those interactions. When the amplitude of imposed tidal stretch (epsilon) was very small, 0.25% of muscle optimal length, the steady-state value of F approximated the isometric force, E was large, and eta was small. When epsilon was increased beyond 1%, however, F and E promptly decreased and eta promptly increased. The muscle could be maintained in these steady, dynamically determined contractile states for as long as the tidal stretches were sustained; when epsilon subsequently decreased back to 0.25%, F, E, and eta returned slowly toward their previous values. The provocative stretch amplitude required to cause active force or muscle stiffness to fall by half, or hysteresivity to double, was slightly greater than 2%. These observations are consistent with a direct effect of stretch upon bridge dynamics in which, with increasing tidal stretch amplitude, the number of actin-myosin interactions decreases and their rate of turnover increases. We conclude that the interactions of myosin with actin are at every instant tending toward those that would prevail in the isometric steady state, but tidal changes of muscle length cause an excess in the rate of detachment. These stretch-induced detachment events can come so fast compared with the rate of attachment that static equilibrium conditions are never attained. If so, then airway lumenal narrowing and the underlying contractile state would be governed by a dynamic mechanical process rather than by a mechanical equilibrium of static forces.

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