Crackles and Wheezes: Agents of Injury?

In the midst of rampant tuberculosis plaguing Europe, René Laennec invented the stethoscope in 1816 as a result of both his genius and respect for patient modesty (1, 2). The auscultation method of ear-on-chest was replaced by a new technology that eventually brought clearer and more uniform sound quality. Since that time, the stethoscope has evolved into the universal symbol of clinical medicine. The World Health Organization estimates 10 million physicians and 20 million nurses worldwide are involved in direct patient care (3). Equipped with stethoscopes, tens of millions of lungs are likely examined every day. For its 200-year history, the stethoscope has been an invaluable tool for pulmonologists to diagnose diseases that produce sounds like crackles and wheezes, which are well known signs of disease. In this note, however, I will explore a novel proposal: that the mechanical events creating these sounds also cause disease. How do mechanical stresses and strains cause disease or injury? This question falls into the general topic of mechanotransduction (4). Mechanically perturbed cells respond in many possible ways: growth, remodeling, altered metabolism, modified gene expression, release of bioactive molecules, membrane rupture, tissue failure, and death. For example, endothelial cells respond to blood flow shear stresses (5), osteocytes to force loading (6), and lung epithelium to inflation and deflation (7). Often, the forces and their responses are part of the natural function, as in newly laid-down matrix in bone or production of surfactant in the lung. However, the forces can also create disease or injury, as in formation of blood clots promoted through endothelium responses or ventilator-induced lung injury (8). In the lung, mechanical perturbations can also create sound, and this poses a particularly interesting thought reversal. Can crackles and wheezes both indicate and cause disease? Let’s take a look at the possibilities. Expiratory wheezes are a sign of obstructed airways, as occur in asthma and emphysema. The airflow couples with the elastic airway walls to create flow-induced oscillations. Mechanically, this is very much like blowing up a balloon, then releasing the air while stretching the outlet and making it squeal. As a reference point, in Figure 1, air flowing at a critical speed, U, through a model flexible airway causes wall oscillations of frequency, f, and wavelength, l, which travel at wave speed c= f3 l (9). The oscillations shake the epithelial cells up and down, as indicated in Figure 1. It is f that we hear, and it covers a wide audible frequency range. For an airway, wheezing also can signify local flow limitation (10). Can these oscillations of the epithelial cells injure them? In a study aimed at snoring and sleep apnea, cultured human bronchial epithelial cells were vibrated at 60 Hz to assess their response (11). The vibratory stimulus triggered an inflammatory cascade, as measured by an increase in IL-8 (interleukin8) release. In a following study, vibrations were applied to the upper airway of an in vivo rat model in a snoring pattern: 1 second of vibration followed by 3 seconds of no vibration (12). Examining the soft palate tissue, it was shown that vibration significantly increased the gene expression of the proinflammatory cytokine TNF-a (tumor necrosis factor-a) and neutrophil attractant chemokine MIP-2 (macrophage inflammatory protein-2), which is a rodent equivalent of human IL-8. So the mechanical stimulus of vibration triggers an early proinflammatory process in respiratory epithelium. For an obstructed airway, vibratory stimulation of epithelial cells already inflamed can contribute to a vicious cycle, because increased inflammation exacerbates bronchoconstriction, provoking more wheezing. Turning to inspiration, airway-related crackles are considered the rupturing of liquid plugs, or menisci, in small airways as they “pop open. ” The sound mechanism is very similar to drinking through a straw