Lung disease is a common feature in patients with A-T and often progresses with age and neurological decline [
20]. Diseases of the respiratory system cause significant morbidity and are a frequent factor or cause of death in the A-T population [
20,
30‐
32]. Several factors contribute to the increased susceptibility to respiratory infections. Immunodeficiency may be one, but not the only, etiology for lung disease in A-T. Low levels of pneumococcal antibodies and diminished levels of IgG subclasses are hallmarks of A-T and associated with respiratory tract infection frequency. However, not all respiratory tract infections in A-T are solely due to immunodeficiency [
13,
32]. Abnormal injury repair, premature aging, systemic inflammation, and oxidative stress are confirmed to contribute to the pathophysiology and disease progression in A-T lung disease and pulmonary disorders [
33]. However, little is known about injury and host protective mechanisms in A-T lung disease. Furthermore, dysphagia in patients with A-T is a well known clinical symptom [
25]. Similar to lung disease, this problem appears to be progressive and the assumption that swallowing function worsens with age is consistent with the progression of neurodegeneration and the bulbar impairments associated with A-T [
5]. The impact of cellular and clinical factors on A-T lung disease is unknown so far. In our study, we investigated a pathogen-independent damage in order to determine differences in host mucosal inflammatory and repair mechanisms in
Atm
-/- mice in comparison to control mice. Interestingly,
Atm
-/-mice did not show any clinical symptoms except for smaller size at birth and a slower growth rate compared to the wild-type littermates [
34]. However, when challenged with hydrochloric acid, causing a disruption in the integrity of the airway epithelial barrier, we showed that
Atm
-/-mice exhibit greater severity of clinical symptoms and mortality rates as well as airway recruitment of peripheral leukocytes, and mount an even stronger immune response characterized by inflammatory biomarkers compared with wild-type mice. This is in accordance with the finding that A-T patients do exhibit elevated serum IL-8 levels, reflecting a systemic inflammation contributing to disease phenotype [
35]. Since weights of the Atm
-/-mice were less in comparison to wild-type mice, initial application of 50 μl hydrochloric acid may have shown a high mortality rate in
Atm
-/-mice due to a higher volume per body weight. So we adjusted the application of hydrochloric acid volume to the body weight of the mice.
Epithelial damage, PMN recruitment and activation of host protective mechanisms are early events in acute mucosal inflammation and ALI/ARDS. In this study, we confirmed the pivotal role of ATM in decreasing the severity of HCl acid-initiated ALI. ATM deficiency favored disruption of epithelial barrier integrity after ALI, as indicated by histological findings, and BALF biomarkers, namely IL-6 and TNF-α. In addition, we found an elevation in lung resistance and reduction in tissue compliance before intratracheal administration of HCl that was not altered after ALI. This data is in accordance with pulmonary function testing (PFT) in A-T patients 12–20 years of age, showing a mixture pattern of obstructive and restrictive lung disease [
21,
24,
36]. The current study explored for the first time the inflammatory response of airway mucosa after injury by HCl. In accordance with human studies showing early structural changes, particulary bronchiectasis and consolidation [
37], our
Atm
-/-mice showed decreased compliance and increased obstruction before musosal injury occurred. This is highly suggestive for the role of ATM for epithelial cell integrity homeostasis.
In other murine models, e.g. an experimental model of colitis, or acute inflammation, ATM deficiency also increases production of pro-inflammatory mediators and regulates leukocyte trafficking to inflammatory sites [
38]. Here, ATM deficiency may have contributed to an increased inflammatory response confirmed by levels of several pro-inflammatory mediators in the injured lung.
On the one hand, neutrophilic invasion into the airways is critical to clear pathogens from the site of infection and suppression of the inflammatory response may increase the risk of infection-related adverse events, on the other hand, neutrophilic activation can cause bystander tissue damage that contributes to the pathogenesis of ALI/ARDS [
39]. To this end, inhibition of PMN function in animal studies attenuates lung injury induced by models of gastric acid aspiration [
40,
41]. In this context our data suggest that ATM is a potent regulator of mucosal repair and can promote an array of protective responses for lung catabasis after mucosal injury.
Together, the differences of mucosal immune response and mucosal repair mechanism in Atm
-/- mice point to the clinical impact of repetitive mucosal injury by non-pathogen associated mucosal damage in order to explain decline in lung function in our A-T patients. Furthermore, ATM may be a critical immunoregulatory factor dampening the deleterious effects of acute HCl-induced inflammation, being mandatory for systemic genomic stability and homeostasis of the lung epithelial barrier.